Is COL6A6 p.Pro89Thr (c.265C>A) pathogenic?

COL6A6 p.Pro89Thr (c.265C>A) is classified Uncertain significance in COL6A6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely benign (0.0956); Rare (popmax 0.264%, mid).

How common is COL6A6 p.Pro89Thr (c.265C>A) in the general population?

COL6A6 p.Pro89Thr (c.265C>A) is rare (popmax 0.264%, mid) (gnomAD).

What do computational predictors say about COL6A6 p.Pro89Thr (c.265C>A)?

AlphaMissense predicts likely benign (score 0.0956) — an in-silico prediction, not a clinical call.

COL6A6 p.Pro89Thr

c.265C>A · rs201577074 · VCV2365074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0956 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.264%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0956	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -8.47	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 1.6	GERP 4.9, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 115 kb · p 0.99 · regional, not allelic
Overall
CADD	21.3	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 0.264% Middle Eastern · 16/6,062 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.0231% 373/1,614,002 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.264%	379
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
Remaining individualsnot grpmax-eligible	0.0368%	2,717
European (non-Finnish)	0.0243%	4,111
South Asian	0.0165%	6,072
Admixed American	0.015%	6,669
African / African-American	0.004%	25,015

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.Pro89Thr
Coding: c.265C>A
MANE Select: NM_001102608
dbSNP: rs201577074
Type: single nucleotide variant
Location: chr3:130563268 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.61
Residue 89: the 'nonhelical region' region; the vwfa 1 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-pro89thr (accessed [today's date]).

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