Martsolf syndrome 1

Summary

Martsolf syndrome 1 (MONDO:8000008) is a disease caused by RAB3GAP2 (GenCC Definitive), with 9 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RAB3GAP2 (GenCC Definitive)
• Cohort genes: 9
• ClinVar variants: 45
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0000221	Furrowed tongue	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000322	Short philtrum	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0002162	Low posterior hairline	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0007477	Abnormal dermatoglyphics	Very frequent (80-99%)
HP:0007495	Prematurely aged appearance	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000248	Brachycephaly	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000601	Hypotelorism	Frequent (30-79%)
HP:0000692	Tooth malposition	Frequent (30-79%)
HP:0001155	Abnormality of the hand	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0008388	Abnormal toenail morphology	Frequent (30-79%)
HP:0009465	Ulnar deviation of finger	Frequent (30-79%)
HP:0009832	Abnormal distal phalanx morphology of finger	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0009738	Abnormality of the antihelix	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Martsolf syndrome 1
Mondo ID	MONDO:8000008
MeSH	C536028
OMIM	212720
Orphanet	1387
DOID	DOID:0111586
SNOMED CT	722380003
UMLS	C5542298
MedGen	1778114
GARD	0003406
Is cancer (heuristic)	no

Also known as: cataract-intellectual disability-hypogonadism syndrome · cataract-mental retardation-hypogonadism · MARTSOLF syndrome · Martsolf syndrome

Data availability: 45 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-intellectual disability › Martsolf syndrome 1

Related subtypes (337): Neu-Laxova syndrome, acrofacial dysostosis, Catania type, aortic arch anomaly-facial dysmorphism-intellectual disability syndrome, blepharonasofacial malformation syndrome, brachydactyly-nystagmus-cerebellar ataxia syndrome, craniofaciofrontodigital syndrome, uveal coloboma-cleft lip and palate-intellectual disability, Ramos-Arroyo syndrome, extrasystoles-short stature-hyperpigmentation-microcephaly syndrome, Floating-Harbor syndrome, Myhre syndrome, hirsutism-skeletal dysplasia-intellectual disability syndrome, Johnson neuroectodermal syndrome, KBG syndrome, trichorhinophalangeal syndrome type II, Lenz-Majewski hyperostotic dwarfism, Bannayan-Riley-Ruvalcaba syndrome, microcephaly-deafness-intellectual disability syndrome, ophthalmoplegia-intellectual disability-lingua scrotalis syndrome, omphalocele syndrome, Shprintzen-Goldberg type, Shprintzen-Goldberg syndrome, Smith-Magenis syndrome, delayed speech-facial asymmetry-strabismus-ear lobe creases syndrome, holoprosencephaly-radial heart renal anomalies syndrome, Wolf-Hirschhorn syndrome, pseudoprogeria syndrome, acrocallosal syndrome, acrofacial dysostosis Rodriguez type, agnathia-otocephaly complex, Stimmler syndrome, anencephaly 1, aniridia-renal agenesis-psychomotor retardation syndrome, Biemond syndrome type 2, bird headed-dwarfism, Montreal type, Bowen-Conradi syndrome, Elsahy-Waters syndrome, C syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, Cohen syndrome, cortical blindness-intellectual disability-polydactyly syndrome, Costello syndrome, temtamy syndrome, cardiocranial syndrome, Pfeiffer type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dubowitz syndrome, Bonnemann-Meinecke-Reich syndrome, epilepsy-telangiectasia syndrome, faciocardiorenal syndrome, fountain syndrome, Fryns syndrome, GAPO syndrome, Hall-Riggs syndrome, Mowat-Wilson syndrome, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, hypospadias-intellectual disability, Goldblatt type syndrome, Stromme syndrome, Johanson-Blizzard syndrome, Kapur-Toriello syndrome, oculocerebrofacial syndrome, Kaufman type, Keutel syndrome, Lambert syndrome, Laurence-Moon syndrome, intellectual disability-spasticity-ectrodactyly syndrome, prominent glabella-microcephaly-hypogenitalism syndrome, Marden-Walker syndrome, microcephaly-glomerulonephritis-marfanoid habitus syndrome, marfanoid habitus-autosomal recessive intellectual disability syndrome, McDonough syndrome, intellectual disability-dysmorphism-hypogonadism-diabetes mellitus syndrome, intellectual disability, Buenos-Aires type, microcephaly-cardiomyopathy syndrome, Say-Barber-Miller syndrome, microcephaly-cervical spine fusion anomalies syndrome, Jawad syndrome, lethal multiple pterygium syndrome, neurofaciodigitorenal syndrome, oculo-palato-cerebral syndrome, Oliver syndrome, lethal omphalocele-cleft palate syndrome, Peters plus syndrome, Pfeiffer-Palm-Teller syndrome, urban-Rogers-Meyer syndrome, Wiedemann-Rautenstrauch syndrome, holoprosencephaly-postaxial polydactyly syndrome, radioulnar synostosis-developmental delay-hypotonia syndrome, Ulbright-Hodes syndrome, microbrachycephaly-ptosis-cleft lip syndrome, Smith-Lemli-Opitz syndrome, congenital heart defect-round face-developmental delay syndrome, Filippi syndrome, upper limb defect-eye and ear abnormalities syndrome, Weaver syndrome, intellectual disability, Wolff type, CHIME syndrome, X-linked intellectual disability-plagiocephaly syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, creatine transporter deficiency, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, chromosome Xp11.23-p11.22 duplication syndrome, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, SSR4-congenital disorder of glycosylation, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability-balding-patella luxation-acromicria syndrome, syndromic X-linked intellectual disability 5, male hypergonadotropic hypogonadism-intellectual disability-skeletal anomalies syndrome, X-linked intellectual disability with marfanoid habitus, N syndrome, pterygium colli-intellectual disability-digital anomalies syndrome, Lowry-MacLean syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, pseudoaminopterin syndrome, acrocardiofacial syndrome, Ayme-Gripp syndrome, Harrod syndrome, fallot complex-intellectual disability-growth delay syndrome, MMEP syndrome, epilepsy-microcephaly-skeletal dysplasia syndrome, Fine-Lubinsky syndrome, intellectual disability-sparse hair-brachydactyly syndrome, colobomatous microphthalmia - obesity - hypogenitalism - intellectual disability syndrome, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, Wiedemann-Steiner syndrome, cerebrooculonasal syndrome, genitopatellar syndrome, intellectual disability-obesity-prognathism-eye and skin anomalies syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, AICA-ribosiduria, Goldberg-Shprintzen syndrome, complex cortical dysplasia with other brain malformations 7, Kleefstra syndrome, Koolen-de Vries syndrome, agammaglobulinemia-microcephaly-craniosynostosis-severe dermatitis syndrome, mandibulofacial dysostosis-microcephaly syndrome, camptodactyly syndrome, Guadalajara type 3, chromosome 15q13.3 microdeletion syndrome, chromosome 6pter-p24 deletion syndrome, Zechi-Ceide syndrome, chromosome 19q13.11 deletion syndrome, chromosome 5p13 duplication syndrome, chromosome 17p13.3 duplication syndrome, syndromic multisystem autoimmune disease due to ITCH deficiency, chromosome 15q24 deletion syndrome, chromosome 17q21.31 duplication syndrome, chromosome 19p13.13 deletion syndrome, THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome, DYRK1A-related intellectual disability syndrome, chromosome 8q21.11 deletion syndrome, microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome, chromosome 16q22 deletion syndrome, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, short ulna-dysmorphism-hypotonia-intellectual disability syndrome, microcephaly-intellectual disability-phalangeal and neurological anomalies syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, Hartsfield-Bixler-Demyer syndrome, developmental and epileptic encephalopathy, 18, severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome, CTCF-related neurodevelopmental disorder, severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome, 8q24.3 microdeletion syndrome, microcephaly-thin corpus callosum-intellectual disability syndrome, macrocephaly-developmental delay syndrome, chromosome 5q12 deletion syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Tatton-Brown-Rahman overgrowth syndrome, orofaciodigital syndrome type 14, Catel-Manzke syndrome, cerebellar-facial-dental syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, Houge-Janssens syndrome 2, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, hypomyelinating leukodystrophy 10, congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, transketolase deficiency, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, tall stature-intellectual disability-renal anomalies syndrome, ZTTK syndrome, short stature-brachydactyly-obesity-global developmental delay syndrome, mucopolysaccharidosis-plus syndrome, hypotonia, ataxia, and delayed development syndrome, caudal appendage-deafness syndrome, arachnodactyly-abnormal ossification-intellectual disability syndrome, ataxia-photosensitivity-short stature syndrome, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, brachydactyly-mesomelia-intellectual disability-heart defects syndrome, cardiofaciocutaneous syndrome, cataract-intellectual disability-anal atresia-urinary defects syndrome, cataract-deafness-hypogonadism syndrome, Coffin-Siris syndrome, intellectual disability-hypoplastic corpus callosum-preauricular tag syndrome, craniodigital syndrome-intellectual disability syndrome, cryptorchidism-arachnodactyly-intellectual disability syndrome, facial dysmorphism-shawl scrotum-joint laxity syndrome, epiphyseal dysplasia-hearing loss-dysmorphism syndrome, Cornelia de Lange syndrome, cleft palate-short stature-vertebral anomalies syndrome, Hennekam syndrome, Hernández-Aguirre Negrete syndrome, holoprosencephaly, dysmorphism-short stature-deafness-disorder of sex development syndrome, 5q14.3 microdeletion syndrome, Kabuki syndrome, ptosis-syndactyly-learning difficulties syndrome, macrocephaly-short stature-paraplegia syndrome, Warburg micro syndrome, microcephaly-seizures-intellectual disability-heart disease syndrome, microcephaly-cleft palate syndrome, microcephaly-microcornea syndrome, Seemanova type, multiple congenital anomalies due to 14q32.2 maternally expressed gene defect, neuroectodermal-endocrine syndrome, Opitz G/BBB syndrome, Xp22.13p22.2 duplication syndrome, short stature-webbed neck-heart disease syndrome, microtriplication 11q24.1, preaxial polydactyly-colobomata-intellectual disability syndrome, blepharophimosis - intellectual disability syndrome, 3MC syndrome, Baraitser-Winter cerebrofrontofacial syndrome, 11p15.4 microduplication syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, intellectual disability-short stature-hypertelorism syndrome, intellectual disability-polydactyly-uncombable hair syndrome, 20p13 microdeletion syndrome, 7p22.1 microduplication syndrome, intellectual disability-hypotonia-brachycephaly-pyloric stenosis-cryptorchidism syndrome, 15q overgrowth syndrome, van Maldergem syndrome, distal 17p13.1 microdeletion syndrome, deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome, muscular hypertrophy-hepatomegaly-polyhydramnios syndrome, aphonia-deafness-retinal dystrophy-bifid halluces-intellectual disability syndrome, spondylocostal dysostosis-hypospadias-intellectual disability syndrome, telecanthus-hypertelorism-strabismus-pes cavus syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, Weaver-Williams syndrome, 20q11.2 microduplication syndrome, 2p13.2 microdeletion syndrome, intellectual disability-seizures-macrocephaly-obesity syndrome, intellectual disability-facial dysmorphism-hand anomalies syndrome, XYLT1-congenital disorder of glycosylation, 3q27.3 microdeletion syndrome, 9q31.1q31.3 microdeletion syndrome, 14q24.1q24.3 microdeletion syndrome, FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome, 13q12.3 microdeletion syndrome, cono-spondylar dysplasia, microcephaly-short stature-intellectual disability-facial dysmorphism syndrome, severe intellectual disability-hypotonia-strabismus-coarse face-planovalgus syndrome, 11q22.2q22.3 microdeletion syndrome, 20q11.2 microdeletion syndrome, 19p13.3 microduplication syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, 1p35.2 microdeletion syndrome, megalencephaly-severe kyphoscoliosis-overgrowth syndrome, intellectual disability-muscle weakness-short stature-facial dysmorphism syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, corpus callosum agenesis-macrocephaly-hypertelorism syndrome, DeSanto-Shinawi syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, Ritscher-Schinzel syndrome, visceral neuropathy-brain anomalies-facial dysmorphism-developmental delay syndrome, brain malformation-congenital heart disease-postaxial polydactyly syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, osteopenia-myopia-hearing loss-intellectual disability-facial dysmorphism syndrome, severe intellectual disability-epilepsy-anal anomalies-distal phalangeal hypoplasia, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, developmental and epileptic encephalopathy, 73, pancreatic agenesis-holoprosencephaly syndrome, oculocerebrodental syndrome, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, KAT6B-related multiple congenital anomalies syndrome, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 16p12.1p12.3 triplication syndrome, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, Gabriele de Vries syndrome, Skraban-Deardorff syndrome, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, Pilarowski-Bjornsson syndrome, glycosylphosphatidylinositol biosynthesis defect 15, multiple congenital anomalies-hypotonia-seizures syndrome, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome, SLC12A2-related developmental delay-intellectual disability-sensorineural deafness syndrome, intellectual disability-early-onset cataract-microcephaly syndrome, cleft palate-congenital heart defect-intellectual disability syndrome, PRC-2 complex-related overgrowth spectrum, orofacial clefting-cardiac anomalies-facial dysmorphism syndrome, severe congenital myelofibrosis-pancytopenia-intellectual disability-neurologic and ophthalmic abnormalities syndrome, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN, intellectual disability-epilepsy-dental anomalies-facial dysmorphism syndrome, 2q13 microdeletion syndrome, 10p13-p14 deletion syndrome, 3q26q28 deletion syndrome, Pitt-Hopkins or Pitt-Hopkins-like syndrome, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

45 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 11 likely pathogenic, 4 pathogenic, 3 likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
265206	NM_000216.4(ANOS1):c.1891C>T (p.Arg631Ter)	ANOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
100787	NM_012414.4(RAB3GAP2):c.1276C>T (p.Arg426Cys)	RAB3GAP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173050	NM_012414.4(RAB3GAP2):c.2488C>T (p.Gln830Ter)	RAB3GAP2	Pathogenic	no assertion criteria provided
1173051	NM_012414.4(RAB3GAP2):c.1955T>A (p.Leu652Ter)	RAB3GAP2	Pathogenic	no assertion criteria provided
1820	NM_012414.4(RAB3GAP2):c.3154G>T (p.Gly1052Cys)	RAB3GAP2	Pathogenic	no assertion criteria provided
1679908	NM_004491.5(ARHGAP35):c.2565C>A (p.Tyr855Ter)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679909	NM_004491.5(ARHGAP35):c.3283_3286delinsT (p.Val1095_Lys1096delinsTer)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679913	NM_004491.5(ARHGAP35):c.3569_3570del (p.Glu1190fs)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679920	NM_004491.5(ARHGAP35):c.325C>T (p.Arg109Ter)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679921	NM_004491.5(ARHGAP35):c.345del (p.Tyr116fs)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679922	NM_004491.5(ARHGAP35):c.352A>T (p.Lys118Ter)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679923	NM_004491.5(ARHGAP35):c.516del (p.Asn173fs)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679924	NM_004491.5(ARHGAP35):c.1800_1803del (p.Val601fs)	ARHGAP35	Likely pathogenic	criteria provided, single submitter
1679912	NM_001030055.2(ARHGAP5):c.2366dup (p.Phe790fs)	ARHGAP5	Likely pathogenic	criteria provided, single submitter
2412696	NM_012414.4(RAB3GAP2):c.2287_2291del (p.Ala762_Gly763insTer)	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
3065738	NM_012414.4(RAB3GAP2):c.3645+1del	RAB3GAP2	Likely pathogenic	criteria provided, single submitter
1679925	NM_004491.5(ARHGAP35):c.3850C>T (p.Arg1284Trp)	ARHGAP35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295643	NM_012414.4(RAB3GAP2):c.3143A>G (p.His1048Arg)	RAB3GAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679903	NM_004491.5(ARHGAP35):c.4049G>A (p.Arg1350Gln)	ARHGAP35	Uncertain significance	criteria provided, single submitter
1679904	NM_004491.5(ARHGAP35):c.4105C>G (p.His1369Asp)	ARHGAP35	Uncertain significance	criteria provided, single submitter
1679905	NM_004491.5(ARHGAP35):c.4235T>C (p.Met1412Thr)	ARHGAP35	Uncertain significance	criteria provided, single submitter
1679910	NM_004491.5(ARHGAP35):c.4255C>T (p.Arg1419Cys)	ARHGAP35	Uncertain significance	criteria provided, single submitter
1679926	NM_004491.5(ARHGAP35):c.3992C>T (p.Pro1331Leu)	ARHGAP35	Uncertain significance	criteria provided, single submitter
1679914	NM_001030055.2(ARHGAP5):c.1504del (p.Tyr502fs)	ARHGAP5	Uncertain significance	criteria provided, single submitter
1679915	NM_023110.3(FGFR1):c.2182G>A (p.Glu728Lys)	FGFR1	Uncertain significance	criteria provided, single submitter
1679916	NM_178822.5(IGSF10):c.182G>A (p.Arg61His)	IGSF10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679917	NM_175737.4(KLB):c.3086A>T (p.Lys1029Ile)	KLB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679918	NM_175737.4(KLB):c.878A>T (p.Lys293Met)	KLB	Uncertain significance	criteria provided, single submitter
1805391	NM_012414.4(RAB3GAP2):c.574A>G (p.Thr192Ala)	RAB3GAP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805398	NM_012414.4(RAB3GAP2):c.1434G>C (p.Trp478Cys)	RAB3GAP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 26 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RAB3GAP2	Definitive	Autosomal recessive	Martsolf syndrome 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB3GAP2	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP2	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:401830	Autosomal recessive spastic paraplegia type 69
SEMA3A	Orphanet:130	Brugada syndrome
SEMA3A	Orphanet:478	Kallmann syndrome
TUBB3	Orphanet:300570	Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation
TUBB3	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBB3	Orphanet:467166	Tubulinopathy-associated dysgyria
FGFR1	Orphanet:168953	Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1	Orphanet:2117	Hartsfield syndrome
FGFR1	Orphanet:220386	Semilobar holoprosencephaly
FGFR1	Orphanet:2396	Encephalocraniocutaneous lipomatosis
FGFR1	Orphanet:251576	Gliosarcoma
FGFR1	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:251615	Pilomyxoid astrocytoma
FGFR1	Orphanet:2645	Osteoglosphonic dysplasia
FGFR1	Orphanet:280200	Microform holoprosencephaly
FGFR1	Orphanet:314950	Primary hypereosinophilic syndrome
FGFR1	Orphanet:3157	Septo-optic dysplasia spectrum
FGFR1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FGFR1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGFR1	Orphanet:478	Kallmann syndrome
FGFR1	Orphanet:93258	Pfeiffer syndrome type 1
FGFR1	Orphanet:93924	Lobar holoprosencephaly
FGFR1	Orphanet:99798	Oligodontia
ANOS1	Orphanet:478	Kallmann syndrome

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAB3GAP2	HGNC:17168	ENSG00000118873	Q9H2M9	Rab3 GTPase-activating protein non-catalytic subunit	gencc,clinvar
SEMA3A	HGNC:10723	ENSG00000075213	Q14563	Semaphorin-3A	clinvar
KLB	HGNC:15527	ENSG00000134962	Q86Z14	Beta-klotho	clinvar
TUBB3	HGNC:20772	ENSG00000258947	Q13509	Tubulin beta-3 chain	clinvar
IGSF10	HGNC:26384	ENSG00000152580	Q6WRI0	Immunoglobulin superfamily member 10	clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
ARHGAP35	HGNC:4591	ENSG00000160007	Q9NRY4	Rho GTPase-activating protein 35	clinvar
ANOS1	HGNC:6211	ENSG00000011201	P23352	Anosmin-1	clinvar
ARHGAP5	HGNC:675	ENSG00000100852	Q13017	Rho GTPase-activating protein 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB3GAP2	Rab3 GTPase-activating protein non-catalytic subunit	Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
SEMA3A	Semaphorin-3A	Involved in the development of the olfactory system and in neuronal control of puberty.
KLB	Beta-klotho	Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis.
TUBB3	Tubulin beta-3 chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.
IGSF10	Immunoglobulin superfamily member 10	Involved in the control of early migration of neurons expressing gonadotropin-releasing hormone (GNRH neurons).
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
ARHGAP35	Rho GTPase-activating protein 35	Rho GTPase-activating protein (GAP).
ANOS1	Anosmin-1	Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex.
ARHGAP5	Rho GTPase-activating protein 5	GTPase-activating protein for Rho family members.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.44

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	3	9.7×	0.009
Kinase	1	3.1×	0.422
Other/Unknown	5	1.0×	0.641

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAB3GAP2	Other/Unknown	no		Rab3GAP2, RAB3GAP2_C, RAB3GAP_N
SEMA3A	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
KLB	Other/Unknown	no		Glyco_hydro_1, GH_hydrolase_sf
TUBB3	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
IGSF10	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
ARHGAP35	Other/Unknown	no		RhoGAP_dom, Small_GTPase, FF_domain
ANOS1	Antibody/Immunoglobulin	yes		FN3_dom, WAP_dom, Ig-like_fold
ARHGAP5	Other/Unknown	no		RhoGAP_dom, FF_domain, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 0.

9 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	2
stromal cell of endometrium	2
buccal mucosa cell	2
calcaneal tendon	2
endothelial cell	2
choroid plexus epithelium	1
dorsal root ganglion	1
lateral nuclear group of thalamus	1
colonic epithelium	1
liver	1
sperm	1
embryo	1
ganglionic eminence	1
cardiac muscle of right atrium	1
kidney epithelium	1
left ovary	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
hair follicle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB3GAP2	295	ubiquitous	marker	choroid plexus epithelium, lateral nuclear group of thalamus, dorsal root ganglion
SEMA3A	194	ubiquitous	marker	stromal cell of endometrium, cortical plate, colonic epithelium
KLB	146	broad	marker	sperm, buccal mucosa cell, liver
TUBB3	144	ubiquitous	marker	cortical plate, ganglionic eminence, embryo
IGSF10	219	broad	marker	cardiac muscle of right atrium, left ovary, kidney epithelium
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon
ARHGAP35	277	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
ANOS1	268	broad	marker	visceral pleura, hair follicle, skeletal muscle tissue of rectus abdominis
ARHGAP5	293	ubiquitous	marker	calcaneal tendon, ventricular zone, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB3	6,797
FGFR1	5,693
SEMA3A	2,069
RAB3GAP2	1,794
ARHGAP35	1,649
ANOS1	1,182
KLB	1,139
ARHGAP5	1,091
IGSF10	810

Intra-cohort edges

A	B	Sources
ANOS1	FGFR1	biogrid_interaction, intact, string_interaction
ANOS1	IGSF10	string_interaction
FGFR1	KLB	biogrid_interaction, intact, string_interaction

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR1	P11362	83
TUBB3	Q13509	28
ARHGAP35	Q9NRY4	6
KLB	Q86Z14	5
ARHGAP5	Q13017	3
RAB3GAP2	Q9H2M9	1
ANOS1	P23352	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEMA3A	Q14563	84.50
IGSF10	Q6WRI0	58.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 155. Enrichment computed across 9 evidence-associated genes (8 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR1c ligand binding and activation	2	190.3×	0.007	FGFR1, ANOS1
Negative regulation of FGFR1 signaling	2	92.1×	0.009	FGFR1, ANOS1
Signaling by FGFR	2	86.5×	0.009	KLB, ANOS1
PI3K Cascade	2	68.0×	0.009	KLB, FGFR1
RND1 GTPase cycle	2	66.4×	0.009	ARHGAP35, ARHGAP5
RND3 GTPase cycle	2	64.9×	0.009	ARHGAP35, ARHGAP5
RND2 GTPase cycle	2	64.9×	0.009	ARHGAP35, ARHGAP5
COPI-independent Golgi-to-ER retrograde traffic	2	51.9×	0.010	RAB3GAP2, TUBB3
RHOD GTPase cycle	2	51.0×	0.010	ARHGAP35, ARHGAP5
RHOJ GTPase cycle	2	50.1×	0.010	ARHGAP35, ARHGAP5
RHOQ GTPase cycle	2	45.3×	0.012	ARHGAP35, ARHGAP5
Signaling by FGFR1 amplification mutants	1	713.8×	0.014	FGFR1
FGFR1 ligand binding and activation	1	713.8×	0.014	ANOS1
RHOB GTPase cycle	2	38.6×	0.014	ARHGAP35, ARHGAP5
RHOG GTPase cycle	2	37.1×	0.014	ARHGAP35, ARHGAP5
RHOC GTPase cycle	2	36.6×	0.014	ARHGAP35, ARHGAP5
Constitutive Signaling by Aberrant PI3K in Cancer	2	31.7×	0.015	KLB, FGFR1
betaKlotho-mediated ligand binding	1	475.8×	0.016	KLB
Downstream signaling of activated FGFR4	1	475.8×	0.016	KLB
RAC3 GTPase cycle	2	29.7×	0.016	ARHGAP35, ARHGAP5
FGFR1c and Klotho ligand binding and activation	1	356.9×	0.019	FGFR1
Signaling by plasma membrane FGFR1 fusions	1	356.9×	0.019	FGFR1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	24.2×	0.019	KLB, FGFR1
RHOA GTPase cycle	2	18.7×	0.031	ARHGAP35, ARHGAP5
IGF1R signaling cascade	1	178.4×	0.031	KLB
Sema4D mediated inhibition of cell attachment and migration	1	178.4×	0.031	ARHGAP35
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	178.4×	0.031	FGFR1
CDC42 GTPase cycle	2	18.1×	0.031	ARHGAP35, ARHGAP5
PIP3 activates AKT signaling	2	16.7×	0.031	KLB, FGFR1
FGFR1b ligand binding and activation	1	158.6×	0.032	FGFR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
axon guidance	4	40.3×	2e-04	SEMA3A, TUBB3, ARHGAP35, ANOS1
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	2	624.1×	2e-04	KLB, FGFR1
regulation of cell size	2	170.2×	0.002	ARHGAP35, ARHGAP5
mammary gland development	2	144.0×	0.002	ARHGAP35, ARHGAP5
positive regulation of mesenchymal cell proliferation	2	133.8×	0.002	FGFR1, ARHGAP5
regulation of axon extension involved in axon guidance	1	936.2×	0.010	SEMA3A
vitamin D3 metabolic process	1	936.2×	0.010	FGFR1
positive regulation of mitotic cell cycle DNA replication	1	936.2×	0.010	FGFR1
positive regulation of parathyroid hormone secretion	1	936.2×	0.010	FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	936.2×	0.010	FGFR1
regulation of phosphate transport	1	624.1×	0.010	FGFR1
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	624.1×	0.010	FGFR1
regulation of lateral mesodermal cell fate specification	1	624.1×	0.010	FGFR1
sensory system development	1	624.1×	0.010	SEMA3A
establishment of protein localization to endoplasmic reticulum membrane	1	624.1×	0.010	RAB3GAP2
basal dendrite arborization	1	624.1×	0.010	SEMA3A
ventricular zone neuroblast division	1	468.1×	0.010	FGFR1
establishment or maintenance of actin cytoskeleton polarity	1	468.1×	0.010	ARHGAP35
negative regulation of fibroblast growth factor production	1	468.1×	0.010	FGFR1
neuron projection guidance	1	468.1×	0.010	ARHGAP35
sympathetic neuron projection guidance	1	468.1×	0.010	SEMA3A
positive regulation of protein lipidation	1	468.1×	0.010	RAB3GAP2
positive regulation of endoplasmic reticulum tubular network organization	1	468.1×	0.010	RAB3GAP2
Rho protein signal transduction	2	55.1×	0.010	ARHGAP35, ARHGAP5
regulation of small GTPase mediated signal transduction	2	32.0×	0.010	ARHGAP35, ARHGAP5
positive regulation of neuron projection development	2	30.4×	0.010	FGFR1, ARHGAP35
neuron migration	2	29.7×	0.010	SEMA3A, FGFR1
positive regulation of phospholipase activity	1	374.5×	0.011	FGFR1
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling	1	374.5×	0.011	FGFR1
diphosphate metabolic process	1	374.5×	0.011	FGFR1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 4 of 9 evidence-associated genes (44%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TUBB3	COLCHICINE
FGFR1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
TUBB3	21	4
RAB3GAP2	0	0
SEMA3A	0	0
KLB	0	0
IGSF10	0	0
ARHGAP35	0	0
ANOS1	0	0
ARHGAP5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB3
VINBLASTINE	4	TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB3
DOCETAXEL	4	TUBB3
NOSCAPINE	4	TUBB3
VINBLASTINE SULFATE	4	TUBB3
PACLITAXEL	4	TUBB3
LEVOFLOXACIN	4	TUBB3
VINORELBINE	4	TUBB3
TIRBANIBULIN	4	TUBB3
PODOFILOX	4	TUBB3
VINCRISTINE	4	TUBB3
DOCETAXEL ANHYDROUS	4	TUBB3
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TUBB3	1,781	Binding:1741, Functional:34, ADMET:6
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
ARHGAP35	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR1	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBB3	1,781
FGFR1	1,465

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
COLCHICINE	4	TUBB3
VINBLASTINE	4	TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB3
DOCETAXEL	4	TUBB3
NOSCAPINE	4	TUBB3
VINBLASTINE SULFATE	4	TUBB3
PACLITAXEL	4	TUBB3
LEVOFLOXACIN	4	TUBB3
VINORELBINE	4	TUBB3
TIRBANIBULIN	4	TUBB3
PODOFILOX	4	TUBB3
VINCRISTINE	4	TUBB3
DOCETAXEL ANHYDROUS	4	TUBB3
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TUBB3, FGFR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ANOS1
D	Druggable family + AlphaFold only, no drug	2	SEMA3A, IGSF10
E	Difficult family or no structure, no drug	4	RAB3GAP2, KLB, ARHGAP35, ARHGAP5

Undrugged target profiles

7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KLB	0	FGFR1
ANOS1	0	FGFR1
RAB3GAP2	0	—
SEMA3A	0	—
IGSF10	0	—
ARHGAP35	1	—
ARHGAP5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.