Is COL15A1 p.Val431Met (c.1291G>A) pathogenic?

COL15A1 p.Val431Met (c.1291G>A) is classified Uncertain significance in COL15A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.0877); Ultra-rare (popmax 0.0571%, sas).

How common is COL15A1 p.Val431Met (c.1291G>A) in the general population?

COL15A1 p.Val431Met (c.1291G>A) is ultra-rare (popmax 0.0571%, sas) (gnomAD).

What do computational predictors say about COL15A1 p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

COL15A1 p.Val431Met

c.1291G>A · rs779626166 · VCV3147219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -8.55	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 -1.3	GERP -4.7
Regional constraint	o/e 0.98	unconstrained · MANE · 126 kb · p 0.29 · regional, not allelic
Overall
CADD	0.623	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 0.0571% South Asian · 52/91,066 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00369% 54/1,461,704 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,751
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)	8.48e-05%	1,179,917

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: COL15A1
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_001855
dbSNP: rs779626166
Type: single nucleotide variant
Location: chr9:99004988 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.68 · 1 PDB
Residue 431: the 'nonhelical region 1 (nc1)' region; the '4 x tandem repeats' region; the 'disordered' region

Full COL15A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL15A1 p.Leu756= Benign ★★ same type
COL15A1 p.Pro1063Leu Benign ★★ same type
COL15A1 p.Ser218= Benign ★★ same type
COL15A1 p.Ala1006Ser Uncertain significance ★ ⚠ same type
COL15A1 p.Ala1115Val Uncertain significance ★ ⚠ same type
COL15A1 p.Ala1148Thr Uncertain significance ★ ⚠ same type
COL15A1 p.Ala1193Val Uncertain significance ★ ⚠ same type
COL15A1 p.Ala1244Ser Uncertain significance ★ ⚠ same type

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/col15a1-p-val431met (accessed [today's date]).

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