Is CAPN8 p.Ile340Phe (c.1018A>T) pathogenic?

CAPN8 p.Ile340Phe (c.1018A>T) is classified Uncertain significance in CAPN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: ambiguous (0.4845); Ultra-rare (popmax 0.022%, eas).

How common is CAPN8 p.Ile340Phe (c.1018A>T) in the general population?

CAPN8 p.Ile340Phe (c.1018A>T) is ultra-rare (popmax 0.022%, eas) (gnomAD).

What do computational predictors say about CAPN8 p.Ile340Phe (c.1018A>T)?

AlphaMissense predicts ambiguous (score 0.4845) — an in-silico prediction, not a clinical call.

CAPN8 p.Ile340Phe

c.1018A>T · rs373951019 · VCV2360460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4845 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4845	ambiguous
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -12.54	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 124 kb · p 0.038 · regional, not allelic
Overall
CADD	24.7	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 0.022% East Asian · 9/40,918 alleles

Filtering AF 0.0114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00277% 43/1,551,414 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0549%	1,821
East Asiangrpmax	0.022%	4,546
European (non-Finnish)	8.72e-05%	1,146,988

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile340Phe
Coding: c.1018A>T
MANE Select: NM_001143962
dbSNP: rs373951019
Type: single nucleotide variant
Location: chr1:223619410 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.15 · 1 PDB
Residue 340: the calpain catalytic domain; a β-strand

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

Similar variants

CAPN8 p.Ile340Asn 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-ile340phe (accessed [today's date]).

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