Is COL6A2 p.Val754Ala (c.2261T>C) pathogenic?

COL6A2 p.Val754Ala (c.2261T>C) is classified Uncertain significance in COL6A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely pathogenic (0.8422); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with COL6A2 p.Val754Ala (c.2261T>C)?

COL6A2 p.Val754Ala (c.2261T>C) is associated with Inborn genetic diseases (ClinVar).

How common is COL6A2 p.Val754Ala (c.2261T>C) in the general population?

COL6A2 p.Val754Ala (c.2261T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL6A2 p.Val754Ala (c.2261T>C)?

AlphaMissense predicts likely pathogenic (score 0.8422) — an in-silico prediction, not a clinical call.

COL6A2 p.Val754Ala

c.2261T>C · VCV4616293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8422 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8422	likely pathogenic
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -10.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL6A2
Protein: p.Val754Ala
Coding: c.2261T>C
MANE Select: NM_001849
Type: single nucleotide variant
Location: chr21:46126076 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 754: the vwfa 2 domain; the 'nonhelical region' region

Full COL6A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL6A2 c.955-2A>G Pathogenic ★★ same condition
COL6A2 p.Glu668Ter Pathogenic ★★ same condition
COL6A2 p.Ala1006Thr Uncertain significance ★★ ⚠ same condition
COL6A2 p.Ala139Ser Uncertain significance ★★ ⚠ same condition
COL6A2 p.Ala191Val Uncertain significance ★★ ⚠ same condition
COL6A2 p.Ala389Ser Uncertain significance ★★ ⚠ same condition
COL6A2 p.Ala673Asp Uncertain significance ★★ ⚠ same condition
COL6A2 p.Ala904Thr 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/col6a2-p-val754ala (accessed [today's date]).

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