Is CAPN8 p.Val291Ala (c.872T>C) pathogenic?

CAPN8 p.Val291Ala (c.872T>C) is classified Uncertain significance in CAPN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.1602); Very rare (popmax 0.00548%, afr).

How common is CAPN8 p.Val291Ala (c.872T>C) in the general population?

CAPN8 p.Val291Ala (c.872T>C) is very rare (popmax 0.00548%, afr) (gnomAD).

What do computational predictors say about CAPN8 p.Val291Ala (c.872T>C)?

AlphaMissense predicts likely benign (score 0.1602) — an in-silico prediction, not a clinical call.

CAPN8 p.Val291Ala

c.872T>C · VCV3995273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00548%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1602	likely benign
REVEL	0.683	pathogenic-leaning
SaProt	LLR -11.02	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.2	GERP 2.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 124 kb · p 0.038 · regional, not allelic
Overall
CADD	26.5	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 0.00548% African / African-American · 4/73,052 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.000258% 4/1,551,626 alleles · very rare

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: CAPN8
Protein: p.Val291Ala
Coding: c.872T>C
MANE Select: NM_001143962
Type: single nucleotide variant
Location: chr1:223622842 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.15 · 1 PDB
Residue 291: the calpain catalytic domain

Full CAPN8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN8 p.Val291Glu Uncertain significance ★ ⚠ same residue
CAPN8 p.Ala112Val Uncertain significance ★ ⚠ same type
CAPN8 p.Ala136Glu Uncertain significance ★ ⚠ same type
CAPN8 p.Ala136Thr Uncertain significance ★ ⚠ same type
CAPN8 p.Ala194Ser Uncertain significance ★ ⚠ same type
CAPN8 p.Ala231Ser Uncertain significance ★ ⚠ same type
CAPN8 p.Ala234Val Uncertain significance ★ ⚠ same type
CAPN8 p.Ala247Val 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/capn8-p-val291ala (accessed [today's date]).

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