Is CAPN15 p.Pro765Leu (c.2294C>T) pathogenic?

CAPN15 p.Pro765Leu (c.2294C>T) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: likely benign (0.1678); Ultra-rare (popmax 0.01%, nfe).

How common is CAPN15 p.Pro765Leu (c.2294C>T) in the general population?

CAPN15 p.Pro765Leu (c.2294C>T) is ultra-rare (popmax 0.01%, nfe) (gnomAD).

What do computational predictors say about CAPN15 p.Pro765Leu (c.2294C>T)?

AlphaMissense predicts likely benign (score 0.1678) — an in-silico prediction, not a clinical call.

CAPN15 p.Pro765Leu

c.2294C>T · rs569692237 · VCV3137117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1678	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -14.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,055 bp · p 0.036 · regional, not allelic
Overall
CADD	25.6	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 0.01% European (non-Finnish) · 118/1,178,524 alleles

Filtering AF 0.00852% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00796%

Overall 0.00859% 138/1,606,838 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.01%	9,988
East Asian	0.00893%	11,194
Remaining individualsnot grpmax-eligible	0.00802%	12,472
South Asian	0.00769%	13,006
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
African / African-American	0.00267%	37,506
Finnishnot grpmax-eligible	0.00171%	58,610

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: CAPN15
Protein: p.Pro765Leu
Coding: c.2294C>T
MANE Select: NM_005632
dbSNP: rs569692237
Type: single nucleotide variant
Location: chr16:551613 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 765: the calpain catalytic domain

Full CAPN15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CAPN15 p.Glu776Ala Uncertain significance ★★ ⚠ same type
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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/capn15-p-pro765leu (accessed [today's date]).

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