Is COL6A3 p.Val650Phe (c.1948G>T) pathogenic?

COL6A3 p.Val650Phe (c.1948G>T) is classified Uncertain significance in COL6A3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-18). AlphaMissense: ambiguous (0.5432); Very rare (popmax 0.00517%, nfe); Associated with dystonia 27.

What condition is associated with COL6A3 p.Val650Phe (c.1948G>T)?

COL6A3 p.Val650Phe (c.1948G>T) is associated with dystonia 27, Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Val650Phe (c.1948G>T) in the general population?

COL6A3 p.Val650Phe (c.1948G>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

How is Primary dystonia, DYT27 type inherited?

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

What do computational predictors say about COL6A3 p.Val650Phe (c.1948G>T)?

AlphaMissense predicts ambiguous (score 0.5432) — an in-silico prediction, not a clinical call.

COL6A3 p.Val650Phe

c.1948G>T · rs149187225 · VCV2200318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Conditions

dystonia 27

Computational evidence

Protein change
AlphaMissense	0.5432	ambiguous
REVEL	0.776	moderately pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.26 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00517% European (non-Finnish) · 61/1,180,014 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00417% 61/1,461,866 alleles · very rare

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.Val650Phe
Coding: c.1948G>T
MANE Select: NM_004369
dbSNP: rs149187225
Type: single nucleotide variant
Location: chr2:237379185 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 650: the 'nonhelical region' region; the vwfa 4 domain

Full COL6A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dystonia 27 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bethlem myopathy 1A

For Primary dystonia, DYT27 type (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Childhood

Similar variants

COL6A3 p.Val650Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
COL6A3 c.3071-2A>G Likely pathogenic ★★ same condition
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-val650phe (accessed [today's date]).

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