Is CAPN3 p.Ile765Val (c.2293A>G) pathogenic?

CAPN3 p.Ile765Val (c.2293A>G) is classified Uncertain significance in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-11-09). AlphaMissense: likely benign (0.1865); Absent from gnomAD v4.1.

How common is CAPN3 p.Ile765Val (c.2293A>G) in the general population?

CAPN3 p.Ile765Val (c.2293A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN3 p.Ile765Val (c.2293A>G)?

AlphaMissense predicts likely benign (score 0.1865) — an in-silico prediction, not a clinical call.

CAPN3 p.Ile765Val

c.2293A>G · rs1555423192 · VCV498199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1865 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1865	likely benign
REVEL	0.632	indeterminate
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPN3
Protein: p.Ile765Val
Coding: c.2293A>G
MANE Select: NM_000070
dbSNP: rs1555423192
Type: single nucleotide variant
Location: chr15:42410913 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 765: the 'domain iv' region; an α-helix

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN3 p.Ile765Asn Uncertain significance ★ ⚠ same residue
CAPN3 p.Ile765Thr Uncertain significance ★ ⚠ same residue
CAPN3 p.Ile765= Likely benign ★ same residue
CAPN3 p.Ile765Asp Uncertain significance ★★ same residue
CAPN3 c.1115+5G>C Pathogenic ★★★ same type
CAPN3 c.1194-2A>G Pathogenic ★★★ same type
CAPN3 c.1194-9A>G Pathogenic ★★★ same type
CAPN3 c.1746-20C>G Pathogenic ★★★ 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/capn3-p-ile765val (accessed [today's date]).

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