Is COL6A1 p.Pro679Ser (c.2035C>T) pathogenic?

COL6A1 p.Pro679Ser (c.2035C>T) is classified Conflicting classifications of pathogenicity in COL6A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-22). AlphaMissense: likely benign (0.0726); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL6A1 p.Pro679Ser (c.2035C>T)?

COL6A1 p.Pro679Ser (c.2035C>T) is associated with Inborn genetic diseases, Bethlem myopathy 1A (ClinVar).

How common is COL6A1 p.Pro679Ser (c.2035C>T) in the general population?

COL6A1 p.Pro679Ser (c.2035C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about COL6A1 p.Pro679Ser (c.2035C>T)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

COL6A1 p.Pro679Ser

c.2035C>T · rs756467809 · VCV497367

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -7.90	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 0.84	GERP 1.2, phastCons 0.008
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.038 · regional, not allelic
Overall
CADD	14.82	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 0.0227% African / African-American · 17/74,908 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0013% 21/1,612,374 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,406
South Asian	0.0033%	30,318
Remaining individualsnot grpmax-eligible	0.0016%	62,438

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: COL6A1
Protein: p.Pro679Ser
Coding: c.2035C>T
MANE Select: NM_001848
dbSNP: rs756467809
Type: single nucleotide variant
Location: chr21:46002039 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.28 · 1 PDB
Residue 679: the vwfa 2 domain; the 'c-terminal globular domain' region

Full COL6A1 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

COL6A1 p.Pro679Ala Uncertain significance ★ ⚠ same residue
COL6A1 c.1002+1G>A Pathogenic ★★ same condition
COL6A1 c.1003-1G>A Pathogenic ★★ same condition
COL6A1 c.1003-2A>C Pathogenic ★★ same condition
COL6A1 c.1003-2A>G Pathogenic ★★ same condition
COL6A1 c.1056+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL6A1 c.1056+1G>C Pathogenic ★★ same condition
COL6A1 c.1056+2T>A 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/col6a1-p-pro679ser (accessed [today's date]).

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