Is COL4A2 p.Gly1663Ser (c.4987G>A) pathogenic?

COL4A2 p.Gly1663Ser (c.4987G>A) is classified Conflicting classifications of pathogenicity in COL4A2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.6241); Ultra-rare (popmax 0.0932%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL4A2 p.Gly1663Ser (c.4987G>A)?

COL4A2 p.Gly1663Ser (c.4987G>A) is associated with Inborn genetic diseases, brain small vessel disease 2A, autosomal dominant (ClinVar).

How common is COL4A2 p.Gly1663Ser (c.4987G>A) in the general population?

COL4A2 p.Gly1663Ser (c.4987G>A) is ultra-rare (popmax 0.0932%, nfe) (gnomAD).

What do computational predictors say about COL4A2 p.Gly1663Ser (c.4987G>A)?

AlphaMissense predicts likely pathogenic (score 0.6241) — an in-silico prediction, not a clinical call.

COL4A2 p.Gly1663Ser

c.4987G>A · rs12877501 · VCV311195

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6241 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0932%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6241	likely pathogenic
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -11.28	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 62 kb · p 6e-16 · regional, not allelic
Overall
CADD	28.5	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 0.0932% European (non-Finnish) · 1,100/1,180,032 alleles

Filtering AF 0.0886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0867%

Overall 0.072% 1,161/1,613,506 alleles · ultra-rare exomes 1,100/1,461,214 · genomes 61/152,292 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0932%	1,073
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0608%	1,645
African / African-American	0.016%	6,254
Admixed American	0.005%	20,007
Finnishnot grpmax-eligible	0.00316%	31,679
South Asian	0.0011%	91,084

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.Gly1663Ser
Coding: c.4987G>A
MANE Select: NM_001846
dbSNP: rs12877501
Type: single nucleotide variant
Location: chr13:110512039 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 1663: the collagen iv nc1 domain; a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brain small vessel disease 2A, autosomal dominant

Similar variants

COL4A2 p.Gly1663Arg Uncertain significance ★ ⚠ same residue
COL4A2 p.Gly1663= Likely benign ★ same residue
COL4A2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A2 p.Gly619Asp Likely pathogenic ★★ same condition
COL4A2 c.2425+3G>A Uncertain significance ★★ same condition
COL4A2 p.Ala370Pro Uncertain significance ★★ ⚠ same condition
COL4A2 p.Ala95Asp Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1069Gln Uncertain significance ★★ ⚠ same condition

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-gly1663ser (accessed [today's date]).

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