Is CAPN15 p.Ala615Ser (c.1843G>T) pathogenic?

CAPN15 p.Ala615Ser (c.1843G>T) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-28). AlphaMissense: likely benign (0.3317); Very rare (popmax 0.0041%, nfe).

How common is CAPN15 p.Ala615Ser (c.1843G>T) in the general population?

CAPN15 p.Ala615Ser (c.1843G>T) is very rare (popmax 0.0041%, nfe) (gnomAD).

What do computational predictors say about CAPN15 p.Ala615Ser (c.1843G>T)?

AlphaMissense predicts likely benign (score 0.3317) — an in-silico prediction, not a clinical call.

CAPN15 p.Ala615Ser

c.1843G>T · rs1228386819 · VCV3137114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0041%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3317	likely benign
REVEL	0.382	indeterminate
SaProt	LLR -7.01	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 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,055 bp · p 0.036 · regional, not allelic
Overall
CADD	34.0	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 0.0041% European (non-Finnish) · 47/1,146,470 alleles

Filtering AF 0.00316% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00283%

Overall 0.00325% 50/1,538,962 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0041%	24,393
African / African-American	0.00274%	36,524
Remaining individualsnot grpmax-eligible	0.00167%	59,842

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.Ala615Ser
Coding: c.1843G>T
MANE Select: NM_005632
dbSNP: rs1228386819
Type: single nucleotide variant
Location: chr16:549615 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 615: the calpain catalytic domain

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

Similar variants

CAPN15 p.Ala615= Likely benign ★★ same residue
CAPN15 p.Ala615Val Uncertain significance ★ ⚠ same residue
CAPN15 c.2192+8C>T Uncertain significance ★★ same type
CAPN15 p.Arg428Trp Uncertain significance ★★ ⚠ same type
CAPN15 p.Arg867Cys Uncertain significance ★★ ⚠ same type
CAPN15 p.Arg867His Uncertain significance ★★ ⚠ same type
CAPN15 p.Cys363Arg Uncertain significance ★★ ⚠ same type
CAPN15 p.Glu776Ala 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/capn15-p-ala615ser (accessed [today's date]).

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