Is COL4A2 p.Ala1526Val (c.4577C>T) pathogenic?

COL4A2 p.Ala1526Val (c.4577C>T) is classified Uncertain significance in COL4A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-16). AlphaMissense: likely pathogenic (0.7654); Ultra-rare (popmax 0.0165%, mid).

How common is COL4A2 p.Ala1526Val (c.4577C>T) in the general population?

COL4A2 p.Ala1526Val (c.4577C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about COL4A2 p.Ala1526Val (c.4577C>T)?

AlphaMissense predicts likely pathogenic (score 0.7654) — an in-silico prediction, not a clinical call.

COL4A2 p.Ala1526Val

c.4577C>T · rs757182846 · VCV2182850

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7654 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7654	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -10.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 62 kb · p 6e-16 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,064 alleles

Filtering AF 0.00288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00196%

Overall 0.00211% 34/1,611,622 alleles · ultra-rare exomes 32/1,459,422 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,064
South Asian	0.00662%	15,098
Admixed American	0.00502%	19,917
Remaining individualsnot grpmax-eligible	0.00481%	20,790
European (non-Finnish)	0.0017%	58,952
African / African-American	0.00133%	74,912

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COL4A2
Protein: p.Ala1526Val
Coding: c.4577C>T
MANE Select: NM_001846
dbSNP: rs757182846
Type: single nucleotide variant
Location: chr13:110506589 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 1526: the collagen iv nc1 domain; a β-strand

Full COL4A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL4A2 p.Ala1526= Benign/Likely benign ★★ same residue
COL4A2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same type
COL4A2 p.Gly1389Arg Pathogenic/Likely pathogenic ★★ same type
COL4A2 p.Gly619Asp Likely pathogenic ★★ same type
COL4A2 c.2425+3G>A Uncertain significance ★★ same type
COL4A2 c.315+5G>A Uncertain significance ★★ same type
COL4A2 c.726+4A>G Uncertain significance ★★ same type
COL4A2 p.Ala1183Val Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/col4a2-p-ala1526val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown