Is COL4A2 p.Pro496= (c.1488G>A) pathogenic?

COL4A2 p.Pro496= (c.1488G>A) is classified Benign in COL4A2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Common (popmax 67.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Pro496= (c.1488G>A)?

COL4A2 p.Pro496= (c.1488G>A) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

COL4A2 p.Pro496=

Q: How common is COL4A2 p.Pro496= (c.1488G>A) in the general population?

COL4A2 p.Pro496= (c.1488G>A) is common (popmax 67.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1488G>A · rs7990214 · VCV311128

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 67.6%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

brain small vessel disease 2A, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.8
Overall
CADD	0.095	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.6% Middle Eastern · 4,093/6,056 alleles

Filtering AF 65.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 65.2%

Overall 57.5% 927,898/1,613,380 alleles · common exomes 840,890/1,461,380 · genomes 87,008/152,000 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	67.6%	1
Amishnot grpmax-eligible	67.6%	1
Ashkenazi Jewishnot grpmax-eligible	66.7%	2
African / African-American	63.8%	2
European (non-Finnish)	60.5%	2
Remaining individualsnot grpmax-eligible	57.5%	2
South Asian	47.8%	2
Finnishnot grpmax-eligible	44.3%	2
Admixed American	41.9%	2
East Asian	18.9%	5

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.Pro496=
Coding: c.1488G>A
MANE Select: NM_001846
dbSNP: rs7990214
Type: single nucleotide variant
Location: chr13:110458826 (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

Disease context

brain small vessel disease 2A, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL4A2 p.Pro496fs Likely pathogenic ★ same residue
COL4A2 p.Pro496Leu Likely benign ★★ ⚠ same residue
COL4A2 p.Pro496Ser 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

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-pro496 (accessed [today's date]).

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