Is CAPN6 p.Glu130Lys (c.388G>A) pathogenic?

CAPN6 p.Glu130Lys (c.388G>A) is classified Uncertain significance in CAPN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1167); Ultra-rare (popmax 0.0175%, afr).

How common is CAPN6 p.Glu130Lys (c.388G>A) in the general population?

CAPN6 p.Glu130Lys (c.388G>A) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about CAPN6 p.Glu130Lys (c.388G>A)?

AlphaMissense predicts likely benign (score 0.1167) — an in-silico prediction, not a clinical call.

CAPN6 p.Glu130Lys

c.388G>A · VCV4648146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1167 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1167	likely benign
REVEL	0.626	indeterminate
SaProt	LLR -7.17	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 4.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 17 kb · p 0.098 · regional, not allelic
Overall
CADD	23.1	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 0.0175% African / African-American · 10/57,290 alleles

Filtering AF 0.00939% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.00091% 11/1,209,171 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,729
European (non-Finnish)	0.000112%	894,063

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.Glu130Lys
Coding: c.388G>A
MANE Select: NM_014289
Type: single nucleotide variant
Location: chrX:111253126 (GRCh38)
Structure: AlphaFold pLDDT 91.57
Residue 130: 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-glu130lys (accessed [today's date]).

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