Is COL6A3 p.Ala606Pro (c.1816G>C) pathogenic?

COL6A3 p.Ala606Pro (c.1816G>C) is classified Uncertain significance in COL6A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-25). AlphaMissense: likely benign (0.1146); Ultra-rare (popmax 0.0312%, eas); Associated with Inborn genetic diseases.

What condition is associated with COL6A3 p.Ala606Pro (c.1816G>C)?

COL6A3 p.Ala606Pro (c.1816G>C) is associated with Inborn genetic diseases, Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Ala606Pro (c.1816G>C) in the general population?

COL6A3 p.Ala606Pro (c.1816G>C) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

What do computational predictors say about COL6A3 p.Ala606Pro (c.1816G>C)?

AlphaMissense predicts likely benign (score 0.1146) — an in-silico prediction, not a clinical call.

COL6A3 p.Ala606Pro

c.1816G>C · rs2077988771 · VCV1970296

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1146	likely benign
REVEL	0.544	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP 0.52
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.26 · regional, not allelic
Overall
CADD	3.374	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 0.0312% East Asian · 14/44,892 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.000929% 15/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,207
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ala606Pro
Coding: c.1816G>C
MANE Select: NM_004369
dbSNP: rs2077988771
Type: single nucleotide variant
Location: chr2:237380996 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 606: the 'nonhelical region' region; the vwfa 3 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 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
COL6A3 c.6309+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL6A3 c.6310-2A>G Pathogenic/Likely 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-ala606pro (accessed [today's date]).

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