autosomal dominant Alport syndrome

Summary

autosomal dominant Alport syndrome (MONDO:0007086) is a disease caused by COL4A3 (GenCC Strong), with 6 cohort genes. The dominant Reactome pathway is Anchoring fibril formation (3 cohort genes).

At a glance

• Causal gene: COL4A3 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 882

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant Alport syndrome
Mondo ID	MONDO:0007086
OMIM	104200
Orphanet	88918
DOID	DOID:0110032
SNOMED CT	717766000
UMLS	C5882663
MedGen	1848787
GARD	0000624
Is cancer (heuristic)	no

Also known as: Alport syndrome 3, autosomal dominant · Alport syndrome dominant type · Alport syndrome, autosomal dominant · renal failure and sensorineural hearing loss

Data availability: 882 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant Alport syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid 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

600 retrieved; paginated sample, class counts are floors:

185 uncertain significance, 165 likely pathogenic, 126 conflicting classifications of pathogenicity, 49 pathogenic/likely pathogenic, 33 pathogenic, 29 likely benign, 7 benign/likely benign, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064607	NM_000091.5(COL4A3):c.2881+1G>A	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1067949	NM_000091.5(COL4A3):c.1114+2T>C	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070961	NM_000091.5(COL4A3):c.522dup (p.Leu175fs)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071745	NM_000091.5(COL4A3):c.1111C>T (p.Gln371Ter)	COL4A3	Pathogenic	criteria provided, single submitter
1075091	NM_000091.5(COL4A3):c.92_95dup (p.Lys34fs)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1177517	NM_000091.5(COL4A3):c.2603G>A (p.Gly868Glu)	COL4A3	Pathogenic	no assertion criteria provided
1185593	NM_000091.5(COL4A3):c.3500G>A (p.Gly1167Glu)	COL4A3	Pathogenic	criteria provided, single submitter
1375749	NM_000091.5(COL4A3):c.3619G>A (p.Gly1207Arg)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1410422	NM_000091.5(COL4A3):c.4265C>G (p.Ser1422Ter)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1422757	NM_000091.5(COL4A3):c.1262del (p.Gly421fs)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441244	NM_000091.5(COL4A3):c.1132G>A (p.Gly378Arg)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455985	NM_000091.5(COL4A3):c.4001G>A (p.Gly1334Glu)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1512833	NM_000091.5(COL4A3):c.2330G>T (p.Gly777Val)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1520952	NM_000091.5(COL4A3):c.4755+1G>A	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17484	NM_000091.5(COL4A3):c.4441C>T (p.Arg1481Ter)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
17492	NM_000091.5(COL4A3):c.3499G>A (p.Gly1167Arg)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
192299	NM_000091.5(COL4A3):c.40_63del (p.Leu14_Leu21del)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
2093215	NM_000091.5(COL4A3):c.3737C>G (p.Ser1246Ter)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2105186	NM_000091.5(COL4A3):c.448del (p.Ala150fs)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222053	NM_000091.5(COL4A3):c.765G>T (p.Thr255=)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224786	NM_000091.5(COL4A3):c.998G>C (p.Gly333Ala)	COL4A3	Pathogenic	criteria provided, single submitter
224788	NM_000091.5(COL4A3):c.4474A>T (p.Ser1492Cys)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
2731165	NM_000091.5(COL4A3):c.1408+1G>C	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066304	NM_000091.5(COL4A3):c.2746+1G>C	COL4A3	Pathogenic	criteria provided, single submitter
3234059	NM_000091.5(COL4A3):c.4357C>T (p.Gln1453Ter)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3235248	NM_000091.5(COL4A3):c.716dup (p.Pro240fs)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3235969	NM_000091.5(COL4A3):c.3324dup (p.Pro1109fs)	COL4A3	Pathogenic	criteria provided, single submitter
3236037	NM_000091.5(COL4A3):c.2657-1G>C	COL4A3	Pathogenic	criteria provided, single submitter
3256861	NM_000091.5(COL4A3):c.889-1G>A	COL4A3	Pathogenic	criteria provided, single submitter
3377030	NM_000091.5(COL4A3):c.3683G>A (p.Gly1228Asp)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 13 · 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
COL4A3	Definitive	Semidominant	Alport syndrome	12
COL4A4	Definitive	Autosomal recessive	autosomal recessive Alport syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL4A3	Orphanet:653722	Digenic Alport syndrome
COL4A3	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
COL4A3	Orphanet:88918	Autosomal dominant Alport syndrome
COL4A3	Orphanet:88919	Autosomal recessive Alport syndrome
COL4A4	Orphanet:653722	Digenic Alport syndrome
COL4A4	Orphanet:88918	Autosomal dominant Alport syndrome
COL4A4	Orphanet:88919	Autosomal recessive Alport syndrome
FARS2	Orphanet:319519	Combined oxidative phosphorylation defect type 14
FARS2	Orphanet:466722	Autosomal recessive spastic paraplegia type 77
COL4A5	Orphanet:1018	X-linked Alport syndrome-diffuse leiomyomatosis
COL4A5	Orphanet:653722	Digenic Alport syndrome
COL4A5	Orphanet:88917	X-linked Alport syndrome
COPA	Orphanet:444092	Autoimmune interstitial lung disease-arthritis syndrome

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL4A3	HGNC:2204	ENSG00000169031	Q01955	Collagen alpha-3(IV) chain	gencc,clinvar
COL4A4	HGNC:2206	ENSG00000081052	P53420	Collagen alpha-4(IV) chain	gencc,clinvar
FARS2	HGNC:21062	ENSG00000145982	O95363	Phenylalanine–tRNA ligase, mitochondrial	clinvar
COL4A5	HGNC:2207	ENSG00000188153	P29400	Collagen alpha-5(IV) chain	clinvar
COPA	HGNC:2230	ENSG00000122218	P53621	Coatomer subunit alpha	clinvar
MFF-DT	HGNC:41067	ENSG00000236432		MFF divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL4A3	Collagen alpha-3(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COL4A4	Collagen alpha-4(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
FARS2	Phenylalanine–tRNA ligase, mitochondrial	Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation.
COL4A5	Collagen alpha-5(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COPA	Coatomer subunit alpha	The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Go…

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.17

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
Scaffold/PPI	1	2.9×	0.458
Enzyme (other)	1	2.0×	0.458
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL4A3	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL4A4	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
FARS2	Enzyme (other)	yes	6.1.1.20	Phenylalanyl-tRNA_Synthase, Phe-tRNA-synth_IIc_mito, Fdx_antiC-bd
COL4A5	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COPA	Scaffold/PPI	no		WD40_rpt, Beta-prop_COPA/B_2nd, Coatomer_asu_C
MFF-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	2
retina	1
skeletal muscle tissue of biceps brachii	1
metanephros cortex	1
renal medulla	1
endothelial cell	1
gluteal muscle	1
triceps brachii	1
lower esophagus muscularis layer	1
mucosa of stomach	1
ventricular zone	1
islet of Langerhans	1
pituitary gland	1
stromal cell of endometrium	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL4A3	233	broad	marker	skeletal muscle tissue of biceps brachii, pigmented layer of retina, retina
COL4A4	187	broad	marker	renal medulla, metanephros cortex, pigmented layer of retina
FARS2	260	ubiquitous	marker	triceps brachii, endothelial cell, gluteal muscle
COL4A5	267	ubiquitous	marker	mucosa of stomach, ventricular zone, lower esophagus muscularis layer
COPA	303	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, pituitary gland
MFF-DT	158		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FARS2	2,506
COPA	2,506
COL4A5	1,738
COL4A3	1,671
COL4A4	1,243
MFF-DT	0

Intra-cohort edges

A	B	Sources
COL4A3	COL4A4	string_interaction
COL4A4	COL4A5	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FARS2	O95363	9
COPA	P53621	3
COL4A3	Q01955	2
COL4A4	P53420	2
COL4A5	P29400	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 6 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
Anchoring fibril formation	3	456.8×	3e-07	COL4A3, COL4A4, COL4A5
Fibronectin matrix formation	3	342.6×	3e-07	COL4A3, COL4A4, COL4A5
Crosslinking of collagen fibrils	3	342.6×	3e-07	COL4A3, COL4A4, COL4A5
Attachment of bacteria to epithelial cells	3	297.9×	4e-07	COL4A3, COL4A4, COL4A5
Laminin interactions	3	228.4×	7e-07	COL4A3, COL4A4, COL4A5
Collagen chain trimerization	3	155.7×	2e-06	COL4A3, COL4A4, COL4A5
Signaling by PDGF	3	152.3×	2e-06	COL4A3, COL4A4, COL4A5
NCAM1 interactions	3	149.0×	2e-06	COL4A3, COL4A4, COL4A5
Assembly of collagen fibrils and other multimeric structures	3	120.2×	3e-06	COL4A3, COL4A4, COL4A5
Collagen degradation	3	105.4×	4e-06	COL4A3, COL4A4, COL4A5
Collagen biosynthesis and modifying enzymes	3	102.3×	4e-06	COL4A3, COL4A4, COL4A5
Non-integrin membrane-ECM interactions	3	92.6×	5e-06	COL4A3, COL4A4, COL4A5
ECM proteoglycans	3	90.2×	5e-06	COL4A3, COL4A4, COL4A5
Integrin cell surface interactions	3	80.6×	6e-06	COL4A3, COL4A4, COL4A5
Mitochondrial tRNA aminoacylation	1	103.8×	0.013	FARS2
tRNA Aminoacylation	1	57.1×	0.023	FARS2
COPI-dependent Golgi-to-ER retrograde traffic	1	22.2×	0.052	COPA
COPI-mediated anterograde transport	1	22.0×	0.052	COPA
Regulation of expression of SLITs and ROBOs	1	13.8×	0.078	COL4A5
Translation	1	12.4×	0.082	FARS2
Metabolism of proteins	1	2.5×	0.344	FARS2

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
collagen fibril organization	3	134.8×	2e-05	COL4A3, COL4A4, COL4A5
glomerular basement membrane development	2	612.8×	4e-05	COL4A3, COL4A4
collagen-activated tyrosine kinase receptor signaling pathway	2	518.5×	4e-05	COL4A3, COL4A5
phenylalanyl-tRNA aminoacylation	1	842.6×	0.004	FARS2
protein localization to cell leading edge	1	842.6×	0.004	COPA
pancreatic juice secretion	1	674.1×	0.004	COPA
protein localization to axon	1	674.1×	0.004	COPA
negative regulation of vascular endothelial cell proliferation	1	674.1×	0.004	COL4A3
endothelial cell apoptotic process	1	259.3×	0.009	COL4A3
tRNA aminoacylation for protein translation	1	168.5×	0.011	FARS2
tRNA processing	1	168.5×	0.011	FARS2
intra-Golgi vesicle-mediated transport	1	105.3×	0.015	COPA
neuromuscular junction development	1	105.3×	0.015	COL4A5
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	67.4×	0.022	COPA
negative regulation of angiogenesis	1	33.7×	0.041	COL4A3
endoplasmic reticulum to Golgi vesicle-mediated transport	1	27.2×	0.048	COPA
sensory perception of sound	1	20.2×	0.060	COL4A3
intracellular protein transport	1	13.0×	0.084	COPA
cell surface receptor signaling pathway	1	12.8×	0.084	COL4A3
negative regulation of cell population proliferation	1	8.4×	0.119	COL4A3
cell adhesion	1	7.5×	0.127	COL4A3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 5 of 6 evidence-associated genes (83%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL4A3	0	0
COL4A4	0	0
FARS2	0	0
COL4A5	0	0
COPA	0	0
MFF-DT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FARS2	3	Binding:3
COPA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FARS2	6.1.1.20	phenylalanine-tRNA ligase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	COL4A3, COL4A4, COL4A5, COPA, MFF-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL4A3	0	—
COL4A4	0	—
FARS2	3	—
COL4A5	0	—
COPA	1	—
MFF-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.