Is COL6A2 p.Pro414Ser (c.1240C>T) pathogenic?

COL6A2 p.Pro414Ser (c.1240C>T) is classified Uncertain significance in COL6A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1136); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL6A2 p.Pro414Ser (c.1240C>T)?

COL6A2 p.Pro414Ser (c.1240C>T) is associated with Inborn genetic diseases, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Pro414Ser (c.1240C>T) in the general population?

COL6A2 p.Pro414Ser (c.1240C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about COL6A2 p.Pro414Ser (c.1240C>T)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

COL6A2 p.Pro414Ser

c.1240C>T · rs764162312 · VCV2963496

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.489	indeterminate
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,858 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,460,196 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: COL6A2
Protein: p.Pro414Ser
Coding: c.1240C>T
MANE Select: NM_001849
dbSNP: rs764162312
Type: single nucleotide variant
Location: chr21:46119090 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 414: the 'triple-helical region' region; the 'disordered' region

Full COL6A2 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

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
COL6A2 c.115+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1180-1G>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/col6a2-p-pro414ser (accessed [today's date]).

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