Is COL6A6 p.Phe232Leu (c.696C>G) pathogenic?

COL6A6 p.Phe232Leu (c.696C>G) is classified Uncertain significance in COL6A6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-21). AlphaMissense: likely pathogenic (0.9267); Absent from gnomAD v4.1.

How common is COL6A6 p.Phe232Leu (c.696C>G) in the general population?

COL6A6 p.Phe232Leu (c.696C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL6A6 p.Phe232Leu (c.696C>G)?

AlphaMissense predicts likely pathogenic (score 0.9267) — an in-silico prediction, not a clinical call.

COL6A6 p.Phe232Leu

c.696C>G · VCV3835422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9267 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9267	likely pathogenic · top 3% in COL6A6
REVEL	0.627	indeterminate
SaProt	LLR -10.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 2.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 115 kb · p 0.99 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: COL6A6
Protein: p.Phe232Leu
Coding: c.696C>G
MANE Select: NM_001102608
Type: single nucleotide variant
Location: chr3:130565028 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.61
Residue 232: the 'nonhelical region' region; the vwfa 2 domain

Full COL6A6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL6A6 p.Phe232Val Uncertain significance ★ ⚠ same residue
COL6A6 p.Arg1295Ter Uncertain significance ★★ same type
COL6A6 p.Arg1864Thr Uncertain significance ★★ ⚠ same type
COL6A6 p.Arg906His Uncertain significance ★★ ⚠ same type
COL6A6 p.Arg937Trp Uncertain significance ★★ ⚠ same type
COL6A6 p.Tyr1805Cys Uncertain significance ★★ ⚠ same type
COL6A6 c.2977+4A>T Benign ★★ same type
COL6A6 c.4273-3C>T Likely benign ★★ same type

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/col6a6-p-phe232leu (accessed [today's date]).

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