Is COL6A6 p.Phe245Ile (c.733T>A) pathogenic?

COL6A6 p.Phe245Ile (c.733T>A) is classified Uncertain significance in COL6A6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.0706); Rare (popmax 0.134%, eas).

How common is COL6A6 p.Phe245Ile (c.733T>A) in the general population?

COL6A6 p.Phe245Ile (c.733T>A) is rare (popmax 0.134%, eas) (gnomAD).

What do computational predictors say about COL6A6 p.Phe245Ile (c.733T>A)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

COL6A6 p.Phe245Ile

c.733T>A · rs202020243 · VCV3147794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -8.35	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 0.28	GERP -0.5, phastCons 0.84
Regional constraint	o/e 1.00	unconstrained · MANE · 115 kb · p 0.99 · regional, not allelic
Overall
CADD	15.16	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 0.134% East Asian · 60/44,890 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0967%

Overall 0.00384% 62/1,613,994 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.134%	748
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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: COL6A6
Protein: p.Phe245Ile
Coding: c.733T>A
MANE Select: NM_001102608
dbSNP: rs202020243
Type: single nucleotide variant
Location: chr3:130565065 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.61
Residue 245: 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.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
COL6A6 p.Ala1876= 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-phe245ile (accessed [today's date]).

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