Is COL4A2 p.Pro649Ser (c.1945C>T) pathogenic?

COL4A2 p.Pro649Ser (c.1945C>T) is classified Benign/Likely benign in COL4A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-08). AlphaMissense: likely benign (0.0712); Rare (popmax 0.125%, eas); Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Pro649Ser (c.1945C>T)?

COL4A2 p.Pro649Ser (c.1945C>T) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

How common is COL4A2 p.Pro649Ser (c.1945C>T) in the general population?

COL4A2 p.Pro649Ser (c.1945C>T) is rare (popmax 0.125%, eas) (gnomAD).

What do computational predictors say about COL4A2 p.Pro649Ser (c.1945C>T)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

COL4A2 p.Pro649Ser

c.1945C>T · rs370641410 · VCV311137

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brain small vessel disease 2A, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 62 kb · p 6e-16 · regional, not allelic
Overall
CADD	17.4	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 0.125% East Asian · 56/44,876 alleles

Filtering AF 0.0986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0892%

Overall 0.00601% 97/1,613,720 alleles · rare exomes 80/1,461,406 · genomes 17/152,314 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.125%	801
South Asian	0.0253%	3,960
Remaining individualsnot grpmax-eligible	0.0208%	4,807
European (non-Finnish)	0.000424%	235,978

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.Pro649Ser
Coding: c.1945C>T
MANE Select: NM_001846
dbSNP: rs370641410
Type: single nucleotide variant
Location: chr13:110465573 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 649: 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 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
COL4A2 p.Arg1069Trp Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1617Gln 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-pro649ser (accessed [today's date]).

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