Is CAPN14 p.Ile56Val (c.166A>G) pathogenic?

CAPN14 p.Ile56Val (c.166A>G) is classified Uncertain significance in CAPN14 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely benign (0.0661); Very rare (popmax 0.00645%, nfe).

How common is CAPN14 p.Ile56Val (c.166A>G) in the general population?

CAPN14 p.Ile56Val (c.166A>G) is very rare (popmax 0.00645%, nfe) (gnomAD).

What do computational predictors say about CAPN14 p.Ile56Val (c.166A>G)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

CAPN14 p.Ile56Val

c.166A>G · rs979380945 · VCV3137091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00645%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -7.14	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 0.65	GERP -0.43, phastCons 0.002
Regional constraint	o/e 1.01	unconstrained · MANE · 31 kb · p 0.76 · regional, not allelic
Overall
CADD	3.994	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 0.00645% European (non-Finnish) · 74/1,146,986 alleles

Filtering AF 0.00526% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00481%

Overall 0.0049% 76/1,550,072 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00645%	15,500
Remaining individualsnot grpmax-eligible	0.00167%	59,958
African / African-American	0.00137%	72,954

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.Ile56Val
Coding: c.166A>G
MANE Select: NM_001145122
dbSNP: rs979380945
Type: single nucleotide variant
Location: chr2:31205282 (GRCh38)
Gene constraint: LOEUF 1.109 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.02
Residue 56: 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-ile56val (accessed [today's date]).

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