Is CAPN6 p.Thr183Ser (c.547A>T) pathogenic?

CAPN6 p.Thr183Ser (c.547A>T) is classified Uncertain significance in CAPN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely benign (0.1125); Ultra-rare (popmax 0.011%, nfe).

How common is CAPN6 p.Thr183Ser (c.547A>T) in the general population?

CAPN6 p.Thr183Ser (c.547A>T) is ultra-rare (popmax 0.011%, nfe) (gnomAD).

What do computational predictors say about CAPN6 p.Thr183Ser (c.547A>T)?

AlphaMissense predicts likely benign (score 0.1125) — an in-silico prediction, not a clinical call.

CAPN6 p.Thr183Ser

c.547A>T · rs201944265 · VCV2472188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1125 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1125	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -2.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 17 kb · p 0.098 · regional, not allelic
Overall
CADD	18.47	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 0.011% European (non-Finnish) · 98/894,747 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00845%

Overall 0.00852% 103/1,209,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.011%	9,130
Remaining individualsnot grpmax-eligible	0.00841%	11,890
African / African-American	0.00175%	57,165

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: CAPN6
Protein: p.Thr183Ser
Coding: c.547A>T
MANE Select: NM_014289
dbSNP: rs201944265
Type: single nucleotide variant
Location: chrX:111252459 (GRCh38)
Structure: AlphaFold pLDDT 91.57
Residue 183: the calpain catalytic domain

Full CAPN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN6 c.1158+128A>T Benign ★★ same type
CAPN6 c.1743+105G>A Benign ★★ same type
CAPN6 c.297+86C>T Benign ★★ same type
CAPN6 c.699+25C>T Benign ★★ same type
CAPN6 c.700-159T>C Benign ★★ same type
CAPN6 p.Tyr117= Benign ★★ same type
CAPN6 p.Val277Leu Benign ★★ same type
CAPN6 p.Arg260Cys Uncertain significance ★ ⚠ 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/capn6-p-thr183ser (accessed [today's date]).

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