Is COL4A2 p.Pro496Ser (c.1486C>T) pathogenic?

COL4A2 p.Pro496Ser (c.1486C>T) is classified Likely benign in COL4A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-07). AlphaMissense: likely benign (0.1035); Ultra-rare (popmax 0.0107%, afr).

How common is COL4A2 p.Pro496Ser (c.1486C>T) in the general population?

COL4A2 p.Pro496Ser (c.1486C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about COL4A2 p.Pro496Ser (c.1486C>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

COL4A2 p.Pro496Ser

c.1486C>T · rs374754168 · VCV1980173

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 62 kb · p 6e-16 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,882 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000682% 11/1,613,820 alleles · ultra-rare exomes 6/1,461,704 · genomes 5/152,116 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,360
Admixed American	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Pro496Ser
Coding: c.1486C>T
MANE Select: NM_001846
dbSNP: rs374754168
Type: single nucleotide variant
Location: chr13:110458824 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 496: the 'triple-helical region' region

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

Similar variants

COL4A2 p.Pro496= Benign ★★ same residue
COL4A2 p.Pro496Leu Likely benign ★★ ⚠ same residue
COL4A2 p.Pro496fs Likely pathogenic ★ 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

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-pro496ser (accessed [today's date]).

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