Is COL6A6 p.Phe707Ile (c.2119T>A) pathogenic?

COL6A6 p.Phe707Ile (c.2119T>A) is classified Uncertain significance in COL6A6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: ambiguous (0.4727); Very rare (popmax 8.48e-05%, nfe).

How common is COL6A6 p.Phe707Ile (c.2119T>A) in the general population?

COL6A6 p.Phe707Ile (c.2119T>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about COL6A6 p.Phe707Ile (c.2119T>A)?

AlphaMissense predicts ambiguous (score 0.4727) — an in-silico prediction, not a clinical call.

COL6A6 p.Phe707Ile

c.2119T>A · rs2472923652 · VCV3147750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4727	ambiguous
REVEL	0.527	indeterminate
SaProt	LLR -13.64	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 115 kb · p 0.99 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,896 alleles

Overall 6.84e-05% 1/1,461,708 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: COL6A6
Protein: p.Phe707Ile
Coding: c.2119T>A
MANE Select: NM_001102608
dbSNP: rs2472923652
Type: single nucleotide variant
Location: chr3:130568322 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.61
Residue 707: the 'nonhelical region' region; the vwfa 4 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-phe707ile (accessed [today's date]).

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