Is CAPN7 p.Ala459Ser (c.1375G>T) pathogenic?

CAPN7 p.Ala459Ser (c.1375G>T) is classified Uncertain significance in CAPN7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.6678); Very rare (popmax 0.00936%, afr).

How common is CAPN7 p.Ala459Ser (c.1375G>T) in the general population?

CAPN7 p.Ala459Ser (c.1375G>T) is very rare (popmax 0.00936%, afr) (gnomAD).

What do computational predictors say about CAPN7 p.Ala459Ser (c.1375G>T)?

AlphaMissense predicts likely pathogenic (score 0.6678) — an in-silico prediction, not a clinical call.

CAPN7 p.Ala459Ser

c.1375G>T · VCV3995258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00936%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6678	likely pathogenic
REVEL	0.665	pathogenic-leaning
SaProt	LLR -10.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 28 kb · p 0.0017 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00936% African / African-American · 7/74,790 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00112% 18/1,612,466 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00936%	10,684
South Asian	0.00771%	12,976
Remaining individualsnot grpmax-eligible	0.00481%	20,800
European (non-Finnish)	8.48e-05%	1,179,391

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: CAPN7
Protein: p.Ala459Ser
Coding: c.1375G>T
MANE Select: NM_014296
Type: single nucleotide variant
Location: chr3:15235113 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.88 · 2 PDB
Residue 459: the calpain catalytic domain

Full CAPN7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN7 c.2073+1G>T Uncertain significance ★ same type
CAPN7 p.Ala10Asp Uncertain significance ★ ⚠ same type
CAPN7 p.Ala10Ser Uncertain significance ★ ⚠ same type
CAPN7 p.Ala149Val Uncertain significance ★ ⚠ same type
CAPN7 p.Ala29Val Uncertain significance ★ ⚠ same type
CAPN7 p.Ala37Thr Uncertain significance ★ ⚠ same type
CAPN7 p.Ala39Asp Uncertain significance ★ ⚠ same type
CAPN7 p.Ala583Thr 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/capn7-p-ala459ser (accessed [today's date]).

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