Is COL6A3 p.Arg425Ser (c.1275G>T) pathogenic?

COL6A3 p.Arg425Ser (c.1275G>T) is classified Uncertain significance in COL6A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-22). AlphaMissense: likely pathogenic (0.5925); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with COL6A3 p.Arg425Ser (c.1275G>T)?

COL6A3 p.Arg425Ser (c.1275G>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL6A3 p.Arg425Ser (c.1275G>T) in the general population?

COL6A3 p.Arg425Ser (c.1275G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about COL6A3 p.Arg425Ser (c.1275G>T)?

AlphaMissense predicts likely pathogenic (score 0.5925) — an in-silico prediction, not a clinical call.

COL6A3 p.Arg425Ser

c.1275G>T · rs370549716 · VCV392033

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5925	likely pathogenic
REVEL	0.591	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.26 · regional, not allelic
Overall
CADD	20.2	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 0.0011% South Asian · 1/90,952 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,613,726 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,476
South Asiangrpmax	0.0011%	90,952
European (non-Finnish)	0.000763%	131,100

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COL6A3
Protein: p.Arg425Ser
Coding: c.1275G>T
MANE Select: NM_004369
dbSNP: rs370549716
Type: single nucleotide variant
Location: chr2:237387619 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 425: the 'nonhelical region' region

Full COL6A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL6A3 c.6282+1G>A Pathogenic ★★ same condition
COL6A3 p.Gly2080Arg Pathogenic/Likely pathogenic ★★ same condition
COL6A3 p.Ala1298Thr Uncertain significance ★★ same condition
COL6A3 p.Ala1356Val Uncertain significance ★★ ⚠ same condition
COL6A3 p.Ala1365Thr Uncertain significance ★★ same condition
COL6A3 p.Ala2665Ser Uncertain significance ★★ ⚠ same condition
COL6A3 p.Ala2755Thr Uncertain significance ★★ ⚠ same condition
COL6A3 p.Ala2964Ser Uncertain significance ★★ ⚠ same condition

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/col6a3-p-arg425ser (accessed [today's date]).

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