Is COL6A3 p.Ala991Val (c.2972C>T) pathogenic?

COL6A3 p.Ala991Val (c.2972C>T) is classified Conflicting classifications of pathogenicity in COL6A3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1111); Rare (popmax 0.115%, mid); Associated with Inborn genetic diseases.

What condition is associated with COL6A3 p.Ala991Val (c.2972C>T)?

COL6A3 p.Ala991Val (c.2972C>T) is associated with Inborn genetic diseases, Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Ala991Val (c.2972C>T) in the general population?

COL6A3 p.Ala991Val (c.2972C>T) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about COL6A3 p.Ala991Val (c.2972C>T)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

COL6A3 p.Ala991Val

c.2972C>T · rs202185764 · VCV476515

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.095	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.55, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.26 · regional, not allelic
Overall
CADD	13.96	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 0.115% Middle Eastern · 7/6,084 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0599%

Overall 0.0133% 215/1,614,068 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
South Asian	0.0801%	1,248
Remaining individualsnot grpmax-eligible	0.0192%	5,207
European (non-Finnish)	0.0101%	9,916
Admixed American	0.00333%	29,998
East Asian	0.00223%	44,896
African / African-American	0.00133%	74,934

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: COL6A3
Protein: p.Ala991Val
Coding: c.2972C>T
MANE Select: NM_004369
dbSNP: rs202185764
Type: single nucleotide variant
Location: chr2:237376870 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 991: the 'nonhelical region' region; the vwfa 5 domain

Full COL6A3 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

Also linked: Bethlem myopathy 1A

Similar variants

COL6A3 p.Ala991= Likely benign ★ same residue
COL6A3 p.Ala991Glu Uncertain significance ★ ⚠ same residue
COL6A3 c.5838+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL6A3 c.6156+1G>A Pathogenic ★★ same condition
COL6A3 c.6157-2A>C Pathogenic ★★ same condition
COL6A3 c.6210+1G>A Pathogenic ★★ same condition
COL6A3 c.6282+1G>A Pathogenic ★★ same condition
COL6A3 c.6309+1G>A Pathogenic ★★ 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/col6a3-p-ala991val (accessed [today's date]).

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