Is CAPN14 p.Ile245Phe (c.733A>T) pathogenic?

CAPN14 p.Ile245Phe (c.733A>T) is classified Uncertain significance in CAPN14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1133); Ultra-rare (popmax 0.0892%, sas).

How common is CAPN14 p.Ile245Phe (c.733A>T) in the general population?

CAPN14 p.Ile245Phe (c.733A>T) is ultra-rare (popmax 0.0892%, sas) (gnomAD).

What do computational predictors say about CAPN14 p.Ile245Phe (c.733A>T)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

CAPN14 p.Ile245Phe

c.733A>T · VCV3995187

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0892%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -9.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.092	GERP -2.9, phastCons 0.006
Regional constraint	o/e 1.01	unconstrained · MANE · 31 kb · p 0.76 · regional, not allelic
Overall
CADD	15.84	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 0.0892% South Asian · 75/84,040 alleles

Filtering AF 0.073% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.067%

Overall 0.0049% 76/1,551,490 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0892%	1,121
Remaining individualsnot grpmax-eligible	0.00166%	60,114

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: CAPN14
Protein: p.Ile245Phe
Coding: c.733A>T
MANE Select: NM_001145122
Type: single nucleotide variant
Location: chr2:31199526 (GRCh38)
Gene constraint: LOEUF 1.109 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.02
Residue 245: the calpain catalytic domain

Full CAPN14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN14 p.Leu185= Benign ★★ same type
CAPN14 p.Ala183Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala255Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala35Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala51Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala613Val Uncertain significance ★ ⚠ same type
CAPN14 p.Arg119Gln Uncertain significance ★ ⚠ same type
CAPN14 p.Arg119Trp 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/capn14-p-ile245phe (accessed [today's date]).

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