Is COL6A2 p.Ser623Phe (c.1868C>T) pathogenic?

COL6A2 p.Ser623Phe (c.1868C>T) is classified Likely pathogenic in COL6A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with Bethlem myopathy 1A.

What condition is associated with COL6A2 p.Ser623Phe (c.1868C>T)?

COL6A2 p.Ser623Phe (c.1868C>T) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Ser623Phe (c.1868C>T) in the general population?

COL6A2 p.Ser623Phe (c.1868C>T) is absent from gnomAD v4.1 (gnomAD).

How is Bethlem muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COL6A2 p.Ser623Phe (c.1868C>T)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

COL6A2 p.Ser623Phe

c.1868C>T · rs2123661865 · VCV1299539

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 1% in COL6A2
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -16.95	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 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	29.9	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

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.Ser623Phe
Coding: c.1868C>T
MANE Select: NM_001849
dbSNP: rs2123661865
Type: single nucleotide variant
Location: chr21:46125516 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 623: the vwfa 2 domain; the 'nonhelical region' region

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

Disease context

Bethlem myopathy 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bethlem muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

COL6A2 p.Ser623= Conflicting classifications of pathogenicity ★ same residue
COL6A2 p.Ser623Cys Uncertain significance ★ ⚠ same residue
COL6A2 c.1000-1G>T Pathogenic ★★ same condition
COL6A2 c.1000-2A>C Pathogenic ★★ same condition
COL6A2 c.1053+1G>A Pathogenic ★★ same condition
COL6A2 c.1053+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1053+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1054-2A>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/col6a2-p-ser623phe (accessed [today's date]).

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