Intellectual disability, autosomal recessive 53

Summary

Intellectual disability, autosomal recessive 53 (MONDO:0014832) is a disease caused by PIGG (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PIGG (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 974
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0030047	Abnormality of lateral ventricle	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0000219	Thin upper lip vermilion	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000445	Wide nose	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001187	Hyperextensibility of the finger joints	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0007258	Severe demyelination of the white matter	Occasional (5-29%)
HP:0008081	Pes valgus	Occasional (5-29%)
HP:0010510	Hypermobility of toe joints	Occasional (5-29%)
HP:0011193	EEG with focal spikes	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 53
Mondo ID	MONDO:0014832
OMIM	616917
Orphanet	488635
UMLS	C4310794
MedGen	934761
GARD	0017897
Is cancer (heuristic)	no

Also known as: congenital disorder of glycosylation due to PIGG deficiency · early-onset epilepsy-intellectual disability-brain anomalies syndrome · glycosylphosphatidylinositol biosynthesis defect 13 · GPIBD13 · intellectual developmental disorder, autosomal recessive 53 · intellectual disability, autosomal recessive 53 · intellectual disability, autosomal recessive type 53 · mental retardation, autosomal recessive 53 · mental retardation, autosomal recessive type 53 · MRT53 · PIGG-CDG

Data availability: 974 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › intellectual disability, autosomal recessive 53

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, 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, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, 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, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel 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, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 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, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

600 retrieved; paginated sample, class counts are floors:

260 likely benign, 252 uncertain significance, 44 pathogenic, 14 benign, 12 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 8 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070482	NC_000004.11:g.(?493125)(998181_?)del	ATP5ME	Pathogenic	criteria provided, single submitter
2423740	NC_000004.11:g.(?520808)(1020391_?)del	ATP5ME	Pathogenic	criteria provided, single submitter
2423747	NC_000004.11:g.(?493125)(663896_?)del	PDE6B	Pathogenic	criteria provided, single submitter
1033296	NM_001127178.3(PIGG):c.1106_1107del (p.Ser368_Tyr369insTer)	PIGG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033708	NM_001127178.3(PIGG):c.2872G>T (p.Glu958Ter)	PIGG	Pathogenic	criteria provided, single submitter
1069220	NM_001127178.3(PIGG):c.309_310del (p.His103fs)	PIGG	Pathogenic	criteria provided, single submitter
1070070	NM_001127178.3(PIGG):c.2288_2289del (p.Tyr763fs)	PIGG	Pathogenic	criteria provided, single submitter
1070171	NM_001127178.3(PIGG):c.624G>A (p.Trp208Ter)	PIGG	Pathogenic	criteria provided, single submitter
1070244	NM_001127178.3(PIGG):c.768_769dup (p.Thr257fs)	PIGG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324904	NM_001127178.3(PIGG):c.2209del (p.Ala737fs)	PIGG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324906	NM_001127178.3(PIGG):c.570+1G>A	PIGG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381176	NM_001127178.3(PIGG):c.1173_1174del (p.Tyr392fs)	PIGG	Pathogenic	criteria provided, single submitter
1387516	NM_001127178.3(PIGG):c.1544_1545del (p.Ala515fs)	PIGG	Pathogenic	criteria provided, single submitter
1396893	NM_001127178.3(PIGG):c.1803del (p.Asp601fs)	PIGG	Pathogenic	criteria provided, single submitter
1401894	NM_001127178.3(PIGG):c.623G>A (p.Trp208Ter)	PIGG	Pathogenic	criteria provided, single submitter
1407970	NC_000004.11:g.(?502598)(509994_?)del	PIGG	Pathogenic	criteria provided, single submitter
1412317	NM_001127178.3(PIGG):c.1733_1734del (p.Trp578fs)	PIGG	Pathogenic	criteria provided, single submitter
1429425	NM_001127178.3(PIGG):c.1231C>T (p.Gln411Ter)	PIGG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453486	NM_001127178.3(PIGG):c.901+1del	PIGG	Pathogenic	criteria provided, multiple submitters, no conflicts
1453903	NM_001127178.3(PIGG):c.1923dup (p.Thr642fs)	PIGG	Pathogenic	criteria provided, single submitter
1457020	NM_001127178.3(PIGG):c.785del (p.Leu262fs)	PIGG	Pathogenic	criteria provided, multiple submitters, no conflicts
1458529	NM_001127178.3(PIGG):c.352C>T (p.Arg118Ter)	PIGG	Pathogenic	criteria provided, single submitter
1459106	NM_001127178.3(PIGG):c.571del	PIGG	Pathogenic	criteria provided, single submitter
1686808	NM_001127178.3(PIGG):c.1640G>A (p.Trp547Ter)	PIGG	Pathogenic	criteria provided, single submitter
1686809	NM_001127178.3(PIGG):c.640C>T (p.His214Tyr)	PIGG	Pathogenic	no assertion criteria provided
1805640	NM_001127178.3(PIGG):c.1956G>A (p.Trp652Ter)	PIGG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805898	NM_001127178.3(PIGG):c.1193C>G (p.Ser398Ter)	PIGG	Pathogenic	criteria provided, single submitter
2005199	NM_001127178.3(PIGG):c.2129_2130del (p.Val710fs)	PIGG	Pathogenic	criteria provided, single submitter
2014469	NM_001127178.3(PIGG):c.768_769del (p.Glu256fs)	PIGG	Pathogenic	criteria provided, single submitter
2061428	NM_001127178.3(PIGG):c.2334del (p.Lys779fs)	PIGG	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 7 · 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
PIGG	Definitive	Autosomal recessive	intellectual disability, autosomal recessive 53	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGG	Orphanet:280	Wolf-Hirschhorn syndrome
PIGG	Orphanet:488635	Early-onset epilepsy-intellectual disability-brain anomalies syndrome
SPTBN1	Orphanet:528084	Non-specific syndromic intellectual disability
SDR9C7	Orphanet:313	Lamellar ichthyosis
SDR9C7	Orphanet:79394	Congenital ichthyosiform erythroderma
PDE6B	Orphanet:714096	Congenital stationary night blindness, Riggs type
PDE6B	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGG	HGNC:25985	ENSG00000174227	Q5H8A4	GPI ethanolamine phosphate transferase 2, catalytic subunit	gencc,clinvar
SPTBN1	HGNC:11275	ENSG00000115306	Q01082	Spectrin beta chain, non-erythrocytic 1	clinvar
SDR9C7	HGNC:29958	ENSG00000170426	Q8NEX9	Short-chain dehydrogenase/reductase family 9C member 7	clinvar
ATP5ME	HGNC:846	ENSG00000169020	P56385	ATP synthase F(0) complex subunit e, mitochondrial	clinvar
PDE6B	HGNC:8786	ENSG00000133256	P35913	Rod cGMP-specific 3’,5’-cyclic phosphodiesterase subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGG	GPI ethanolamine phosphate transferase 2, catalytic subunit	Catalytic subunit of the ethanolamine phosphate transferase 2 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the second alpha-1,6-linked mannose of a 2-acyl-6-[6-phospho…
SPTBN1	Spectrin beta chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
SDR9C7	Short-chain dehydrogenase/reductase family 9C member 7	Plays a crucial role in the formation of the epidermal permeability barrier.
ATP5ME	ATP synthase F(0) complex subunit e, mitochondrial	Subunit e, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…
PDE6B	Rod cGMP-specific 3’,5’-cyclic phosphodiesterase subunit beta	Rod-specific cGMP phosphodiesterase that catalyzes the hydrolysis of 3’,5’-cyclic GMP.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Phosphatase	1	16.8×	0.233
Scaffold/PPI	1	3.5×	0.515
Transcription factor	1	1.6×	0.634
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGG	Phosphatase	yes		Phosphodiest/P_Trfase, Alkaline_phosphatase_core_sf, PIG-G_N
SPTBN1	Scaffold/PPI	no		Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_dom
SDR9C7	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
ATP5ME	Other/Unknown	no		ATP_synth_F0_esu_mt
PDE6B	Transcription factor	no		PDEase_catalytic_dom, GAF, HD/PDEase_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
lower esophagus	1
muscle layer of sigmoid colon	1
endothelial cell	1
skin of hip	1
trigeminal ganglion	1
skin of abdomen	1
skin of leg	1
zone of skin	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
C1 segment of cervical spinal cord	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGG	276	ubiquitous	marker	right uterine tube, muscle layer of sigmoid colon, lower esophagus
SPTBN1	295	ubiquitous	marker	endothelial cell, trigeminal ganglion, skin of hip
SDR9C7	113	tissue_specific	yes	skin of leg, skin of abdomen, zone of skin
ATP5ME	295	ubiquitous	marker	apex of heart, cardiac ventricle, heart left ventricle
PDE6B	183	broad	marker	C1 segment of cervical spinal cord, right uterine tube, spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPTBN1	2,432
ATP5ME	1,979
PIGG	1,484
PDE6B	1,375
SDR9C7	785

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP5ME	P56385	10
SPTBN1	Q01082	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SDR9C7	Q8NEX9	93.41
PDE6B	P35913	89.72
PIGG	Q5H8A4	83.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FLT3 signaling in disease	1	228.4×	0.057	SPTBN1
Activation of the phototransduction cascade	1	190.3×	0.057	PDE6B
Synthesis of glycosylphosphatidylinositol (GPI)	1	126.9×	0.057	PIGG
Formation of ATP by chemiosmotic coupling	1	114.2×	0.057	ATP5ME
Signaling by FLT3 fusion proteins	1	114.2×	0.057	SPTBN1
The canonical retinoid cycle in rods (twilight vision)	1	103.8×	0.057	SDR9C7
Nephrin family interactions	1	95.2×	0.057	SPTBN1
Interaction between L1 and Ankyrins	1	73.7×	0.057	SPTBN1
Cristae formation	1	69.2×	0.057	ATP5ME
Inactivation, recovery and regulation of the phototransduction cascade	1	63.4×	0.057	PDE6B
Sensory processing of sound	1	61.7×	0.057	SPTBN1
RHOV GTPase cycle	1	57.1×	0.057	SPTBN1
RHOU GTPase cycle	1	55.7×	0.057	SPTBN1
NCAM signaling for neurite out-growth	1	54.4×	0.057	SPTBN1
Sensory processing of sound by outer hair cells of the cochlea	1	40.8×	0.071	SPTBN1
Ca2+ pathway	1	35.7×	0.074	PDE6B
Mitochondrial biogenesis	1	33.6×	0.074	ATP5ME
Sensory processing of sound by inner hair cells of the cochlea	1	32.6×	0.074	SPTBN1
Cell-Cell communication	1	27.5×	0.079	SPTBN1
ER to Golgi Anterograde Transport	1	26.6×	0.079	SPTBN1
MAPK1/MAPK3 signaling	1	26.2×	0.079	SPTBN1
L1CAM interactions	1	24.0×	0.082	SPTBN1
COPI-mediated anterograde transport	1	22.0×	0.084	SPTBN1
MAPK family signaling cascades	1	20.6×	0.084	SPTBN1
Transport to the Golgi and subsequent modification	1	20.6×	0.084	SPTBN1
Sensory Perception	1	19.0×	0.087	SPTBN1
Aerobic respiration and respiratory electron transport	1	17.7×	0.090	ATP5ME
Organelle biogenesis and maintenance	1	13.2×	0.114	ATP5ME
RAF/MAP kinase cascade	1	12.2×	0.114	SPTBN1
Asparagine N-linked glycosylation	1	12.0×	0.114	SPTBN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
central nervous system formation	1	1685.2×	0.005	SPTBN1
regulation of SMAD protein signal transduction	1	1685.2×	0.005	SPTBN1
retinal cell apoptotic process	1	1685.2×	0.005	PDE6B
membrane assembly	1	842.6×	0.007	SPTBN1
actin filament capping	1	306.4×	0.015	SPTBN1
phototransduction, visible light	1	259.3×	0.015	PDE6B
plasma membrane organization	1	177.4×	0.017	SPTBN1
proton motive force-driven ATP synthesis	1	160.5×	0.017	ATP5ME
entrainment of circadian clock by photoperiod	1	146.5×	0.017	PDE6B
regulation of protein localization to plasma membrane	1	129.6×	0.017	SPTBN1
negative regulation of cAMP/PKA signal transduction	1	120.4×	0.017	PDE6B
Golgi to plasma membrane protein transport	1	105.3×	0.017	SPTBN1
GPI anchor biosynthetic process	1	99.1×	0.017	PIGG
retinol metabolic process	1	99.1×	0.017	SDR9C7
positive regulation of interleukin-2 production	1	93.6×	0.017	SPTBN1
steroid metabolic process	1	67.4×	0.022	SDR9C7
positive regulation of protein localization to plasma membrane	1	54.4×	0.023	SPTBN1
proton motive force-driven mitochondrial ATP synthesis	1	52.7×	0.023	ATP5ME
mitotic cytokinesis	1	51.9×	0.023	SPTBN1
retina development in camera-type eye	1	51.1×	0.023	PDE6B
central nervous system development	1	23.1×	0.049	SPTBN1
protein localization to plasma membrane	1	21.7×	0.049	SPTBN1
visual perception	1	15.9×	0.062	PDE6B
actin cytoskeleton organization	1	15.8×	0.062	SPTBN1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
PDE6B	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE6B	6	4
SPTBN1	1	2
PIGG	0	0
SDR9C7	0	0
ATP5ME	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE6B
SILDENAFIL	4	PDE6B
TADALAFIL	4	PDE6B
DIPYRIDAMOLE	4	PDE6B
MOLIBRESIB	2	SPTBN1
ZAPRINAST	2	PDE6B
TBA-7371	2	PDE6B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PDE6B	57	Binding:54, ADMET:3
SPTBN1	7	Binding:7
ATP5ME	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

7 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)
VARDENAFIL	4	PDE6B
SILDENAFIL	4	PDE6B
TADALAFIL	4	PDE6B
DIPYRIDAMOLE	4	PDE6B
MOLIBRESIB	2	SPTBN1
ZAPRINAST	2	PDE6B
TBA-7371	2	PDE6B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE6B
B	Phased (≥1) drug, not yet approved	1	SPTBN1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PIGG
E	Difficult family or no structure, no drug	2	SDR9C7, ATP5ME

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGG	0	—
SDR9C7	0	—
ATP5ME	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.