Is COL15A1 p.Lys681Met (c.2042A>T) pathogenic?

COL15A1 p.Lys681Met (c.2042A>T) is classified Uncertain significance in COL15A1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-10-25). AlphaMissense: likely benign (0.3295); Very rare (popmax 0.00356%, nfe).

How common is COL15A1 p.Lys681Met (c.2042A>T) in the general population?

COL15A1 p.Lys681Met (c.2042A>T) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about COL15A1 p.Lys681Met (c.2042A>T)?

AlphaMissense predicts likely benign (score 0.3295) — an in-silico prediction, not a clinical call.

COL15A1 p.Lys681Met

c.2042A>T · rs140757478 · VCV2408134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3295	likely benign
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -11.63	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Pangolin	Δ0.52	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 126 kb · p 0.29 · regional, not allelic
Overall
CADD	30.0	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 0.00356% European (non-Finnish) · 42/1,178,494 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00237%

Overall 0.00261% 42/1,610,532 alleles · very rare

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.Lys681Met
Coding: c.2042A>T
MANE Select: NM_001855
dbSNP: rs140757478
Type: single nucleotide variant
Location: chr9:99025965 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.68 · 1 PDB
Residue 681: the collagen-like 2 domain; the 'disordered' region; the 'triple-helical region 2 (col2)' 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-lys681met (accessed [today's date]).

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