Is COL4A2 p.Val192Phe (c.574G>T) pathogenic?

COL4A2 p.Val192Phe (c.574G>T) is classified Benign/Likely benign in COL4A2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1164); Low-frequency (popmax 3.05%, amr); Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Val192Phe (c.574G>T)?

COL4A2 p.Val192Phe (c.574G>T) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

How common is COL4A2 p.Val192Phe (c.574G>T) in the general population?

COL4A2 p.Val192Phe (c.574G>T) is low-frequency (popmax 3.05%, amr) (gnomAD).

What do computational predictors say about COL4A2 p.Val192Phe (c.574G>T)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

COL4A2 p.Val192Phe

c.574G>T · rs62621885 · VCV311106

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.05%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

brain small vessel disease 2A, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.6, phastCons 0.99
Regional constraint	o/e 0.95	unconstrained · MANE · 143 kb · p 0.24 · regional, not allelic
Overall
CADD	12.57	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 3.05% Admixed American · 1,831/60,010 alleles

Filtering AF 2.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.89%

Overall 0.859% 13,866/1,614,134 alleles · low-frequency exomes 12,758/1,461,836 · genomes 1,108/152,298 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	3.05%	33
South Asian	1.65%	61
European (non-Finnish)	0.831%	120
Remaining individualsnot grpmax-eligible	0.722%	139
Middle Eastern	0.38%	263
African / African-American	0.219%	458
Finnishnot grpmax-eligible	0.0906%	1,104
Ashkenazi Jewishnot grpmax-eligible	0.0743%	1,346
East Asian	0.0267%	3,740

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.Val192Phe
Coding: c.574G>T
MANE Select: NM_001846
dbSNP: rs62621885
Type: single nucleotide variant
Location: chr13:110430425 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 192: a UniProt-annotated variant site (does not affect col4a2 and col4a1 secretion); the 'disordered' region; 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.Val192= Benign/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
COL4A2 p.Arg1069Trp 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-val192phe (accessed [today's date]).

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