Is COL4A2 p.Pro781= (c.2343C>T) pathogenic?

COL4A2 p.Pro781= (c.2343C>T) is classified Conflicting classifications of pathogenicity in COL4A2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-27). Very rare (popmax 0.00833%, amr); Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Pro781= (c.2343C>T)?

COL4A2 p.Pro781= (c.2343C>T) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

How common is COL4A2 p.Pro781= (c.2343C>T) in the general population?

COL4A2 p.Pro781= (c.2343C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

COL4A2 p.Pro781=

c.2343C>T · rs767050469 · VCV745618

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 -3.1
Overall
CADD	1.049	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 4/48,002 alleles

Filtering AF 0.00284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00171%

Overall 0.00202% 31/1,536,076 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
African / African-American	0.00554%	18,045
South Asian	0.0037%	26,997
Remaining individualsnot grpmax-eligible	0.0017%	58,962
European (non-Finnish)	0.00166%	60,074

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.Pro781=
Coding: c.2343C>T
MANE Select: NM_001846
dbSNP: rs767050469
Type: single nucleotide variant
Location: chr13:110473068 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 781: the 'triple-helical region' region; the 'disordered' 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.Pro781Arg Uncertain significance ★ ⚠ same residue
COL4A2 p.Pro781Ser Uncertain significance ★ ⚠ 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-pro781 (accessed [today's date]).

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