Is COL6A5 p.Arg752Trp (c.2254C>T) pathogenic?

COL6A5 p.Arg752Trp (c.2254C>T) is classified Uncertain significance in COL6A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: ambiguous (0.3928); Ultra-rare (popmax 0.0124%, afr).

How common is COL6A5 p.Arg752Trp (c.2254C>T) in the general population?

COL6A5 p.Arg752Trp (c.2254C>T) is ultra-rare (popmax 0.0124%, afr) (gnomAD).

What do computational predictors say about COL6A5 p.Arg752Trp (c.2254C>T)?

AlphaMissense predicts ambiguous (score 0.3928) — an in-silico prediction, not a clinical call.

COL6A5 p.Arg752Trp

c.2254C>T · rs1393082594 · VCV3147711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3928 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, afr)

Computational evidence

Protein change
AlphaMissense	0.3928	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -14.16	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP -3.2, phastCons 0.84
Overall
CADD	25.3	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 0.0124% African / African-American · 9/72,872 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00479%

Overall 0.00168% 26/1,547,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0124%	8,097
Finnishnot grpmax-eligible	0.00503%	19,900
Admixed American	0.00198%	50,398
South Asian	0.0012%	83,536
European (non-Finnish)	0.00105%	95,449

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: COL6A5
Protein: p.Arg752Trp
Coding: c.2254C>T
MANE Select: NM_001278298
dbSNP: rs1393082594
Type: single nucleotide variant
Location: chr3:130388972 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 70.94
Residue 752: the 'nonhelical region' region; the vwfa 4 domain

Full COL6A5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL6A5 p.Ala2589Thr Benign ★★ same type
COL6A5 p.Asn641His Benign ★★ same type
COL6A5 p.Asp160= Benign ★★ same type
COL6A5 p.Glu2272Ter Benign ★★ same type
COL6A5 p.Lys620= Benign ★★ same type
COL6A5 p.Ser1539Thr Benign ★★ same type
COL6A5 p.Thr572= Benign ★★ same type
COL6A5 p.Val2425Ile 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/col6a5-p-arg752trp (accessed [today's date]).

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