Alport syndrome 3b, autosomal recessive

Summary

Alport syndrome 3b, autosomal recessive (MONDO:0957811) is a disease caused by COL4A3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: COL4A3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 489

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Alport syndrome 3b, autosomal recessive
Mondo ID	MONDO:0957811
OMIM	620536
UMLS	C5882699
MedGen	1848447
GARD	0026876
Is cancer (heuristic)	no

Data availability: 489 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Alport syndrome › Alport syndrome 3b, autosomal recessive

Related subtypes (4): autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, X-linked Alport syndrome, digenic Alport 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

489 retrieved; paginated sample, class counts are floors:

152 uncertain significance, 133 likely pathogenic, 113 conflicting classifications of pathogenicity, 64 pathogenic/likely pathogenic, 25 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1008517	NM_000091.5(COL4A3):c.1229G>A (p.Gly410Glu)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070841	NM_000091.5(COL4A3):c.467del (p.Lys156fs)	COL4A3	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
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
1494752	NM_000091.5(COL4A3):c.688-1G>A	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
1685654	NM_000091.5(COL4A3):c.3337+1G>A	COL4A3	Pathogenic	criteria provided, single submitter
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
2444399	NM_000091.5(COL4A3):c.2863G>A (p.Gly955Arg)	COL4A3	Pathogenic/Likely 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
2823561	NM_000091.5(COL4A3):c.829-2A>G	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
3250484	NM_000091.5(COL4A3):c.1526T>A (p.Leu509Ter)	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
3391006	NM_000091.5(COL4A3):c.172_178dup (p.Pro60fs)	COL4A3	Pathogenic	no assertion criteria provided
3391151	NM_000091.5(COL4A3):c.2374G>A (p.Gly792Arg)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3586030	NM_000091.5(COL4A3):c.1820del (p.Pro607fs)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3586038	NM_000091.5(COL4A3):c.2008C>T (p.Gln670Ter)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3586074	NM_000091.5(COL4A3):c.2980+2T>G	COL4A3	Pathogenic	criteria provided, single submitter
3586120	NM_000091.5(COL4A3):c.3620G>T (p.Gly1207Val)	COL4A3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 4 · 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

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

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL4A3	HGNC:2204	ENSG00000169031	Q01955	Collagen alpha-3(IV) chain	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL4A3	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
MFF-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	1
retina	1
skeletal muscle tissue of biceps brachii	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
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: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A3	1,671
MFF-DT	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL4A3	Q01955	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 evidence-associated genes (1 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 1 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	1	761.3×	0.007	COL4A3
Fibronectin matrix formation	1	571.0×	0.007	COL4A3
Crosslinking of collagen fibrils	1	571.0×	0.007	COL4A3
Attachment of bacteria to epithelial cells	1	496.5×	0.007	COL4A3
Laminin interactions	1	380.7×	0.007	COL4A3
Collagen chain trimerization	1	259.6×	0.007	COL4A3
Signaling by PDGF	1	253.8×	0.007	COL4A3
NCAM1 interactions	1	248.3×	0.007	COL4A3
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.007	COL4A3
Collagen degradation	1	175.7×	0.007	COL4A3
Collagen biosynthesis and modifying enzymes	1	170.4×	0.007	COL4A3
Non-integrin membrane-ECM interactions	1	154.3×	0.007	COL4A3
ECM proteoglycans	1	150.3×	0.007	COL4A3
Integrin cell surface interactions	1	134.3×	0.007	COL4A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of vascular endothelial cell proliferation	1	3370.4×	0.002	COL4A3
glomerular basement membrane development	1	1532.0×	0.002	COL4A3
collagen-activated tyrosine kinase receptor signaling pathway	1	1296.3×	0.002	COL4A3
endothelial cell apoptotic process	1	1296.3×	0.002	COL4A3
collagen fibril organization	1	224.7×	0.009	COL4A3
negative regulation of angiogenesis	1	168.5×	0.010	COL4A3
sensory perception of sound	1	100.9×	0.014	COL4A3
cell surface receptor signaling pathway	1	64.1×	0.020	COL4A3
negative regulation of cell population proliferation	1	42.1×	0.026	COL4A3
cell adhesion	1	37.5×	0.027	COL4A3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
MFF-DT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL4A3, MFF-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL4A3	0	—
MFF-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.