Is CAPN8 p.Ile88Phe (c.262A>T) pathogenic?

CAPN8 p.Ile88Phe (c.262A>T) is classified Uncertain significance in CAPN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.1854); Very rare (popmax 0.00274%, afr).

How common is CAPN8 p.Ile88Phe (c.262A>T) in the general population?

CAPN8 p.Ile88Phe (c.262A>T) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about CAPN8 p.Ile88Phe (c.262A>T)?

AlphaMissense predicts likely benign (score 0.1854) — an in-silico prediction, not a clinical call.

CAPN8 p.Ile88Phe

c.262A>T · rs956587673 · VCV2339867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1854	likely benign
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -9.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 124 kb · p 0.038 · regional, not allelic
Overall
CADD	23.1	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 0.00274% African / African-American · 2/73,010 alleles

Filtering AF 0.000455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.00131% 2/152,136 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.Ile88Phe
Coding: c.262A>T
MANE Select: NM_001143962
dbSNP: rs956587673
Type: single nucleotide variant
Location: chr1:223654375 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.15 · 1 PDB
Residue 88: the calpain catalytic domain

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

Similar variants

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
CAPN8 p.Ala248Ser 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-ile88phe (accessed [today's date]).

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