Is COL4A2 p.Ala370Pro (c.1108G>C) pathogenic?

COL4A2 p.Ala370Pro (c.1108G>C) is classified Uncertain significance in COL4A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-04). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.0371%, mid); Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Ala370Pro (c.1108G>C)?

COL4A2 p.Ala370Pro (c.1108G>C) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

How common is COL4A2 p.Ala370Pro (c.1108G>C) in the general population?

COL4A2 p.Ala370Pro (c.1108G>C) is ultra-rare (popmax 0.0371%, mid) (gnomAD).

What do computational predictors say about COL4A2 p.Ala370Pro (c.1108G>C)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

COL4A2 p.Ala370Pro

c.1108G>C · rs909040713 · VCV883509

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0371%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brain small vessel disease 2A, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -4.53	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 -0.86	GERP -2.5
Regional constraint	o/e 0.95	unconstrained · MANE · 143 kb · p 0.24 · regional, not allelic
Overall
CADD	6.012	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0371% Middle Eastern · 2/5,394 alleles

Filtering AF 0.00658% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00347%

Overall 0.00103% 16/1,549,956 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0371%	2,697
Admixed American	0.0118%	8,482
African / African-American	0.00274%	36,487
South Asian	0.00119%	84,004
European (non-Finnish)	0.000436%	229,284

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.Ala370Pro
Coding: c.1108G>C
MANE Select: NM_001846
dbSNP: rs909040713
Type: single nucleotide variant
Location: chr13:110449708 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 370: 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 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.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
COL4A2 p.Arg1704Leu 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-ala370pro (accessed [today's date]).

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