Is CAPN15 p.Ser613Leu (c.1838C>T) pathogenic?

CAPN15 p.Ser613Leu (c.1838C>T) is classified Conflicting classifications of pathogenicity in CAPN15 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-09-19). AlphaMissense: likely pathogenic (0.9802); Very rare (popmax 0.00111%, nfe); Associated with CAPN15-related disorder.

What condition is associated with CAPN15 p.Ser613Leu (c.1838C>T)?

CAPN15 p.Ser613Leu (c.1838C>T) is associated with CAPN15-related disorder, oculogastrointestinal-neurodevelopmental syndrome (ClinVar).

How common is CAPN15 p.Ser613Leu (c.1838C>T) in the general population?

CAPN15 p.Ser613Leu (c.1838C>T) is very rare (popmax 0.00111%, nfe) (gnomAD).

What do computational predictors say about CAPN15 p.Ser613Leu (c.1838C>T)?

AlphaMissense predicts likely pathogenic (score 0.9802) — an in-silico prediction, not a clinical call.

CAPN15 p.Ser613Leu

c.1838C>T · rs374949685 · VCV1074293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CAPN15-related disorder

Computational evidence

Protein change
AlphaMissense	0.9802	likely pathogenic
REVEL	0.449	indeterminate
SaProt	LLR -14.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,055 bp · p 0.036 · regional, not allelic
Overall
CADD	29.1	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 0.00111% European (non-Finnish) · 13/1,174,810 alleles

Filtering AF 0.000617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000476%

Overall 0.000817% 13/1,590,254 alleles · very rare

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.Ser613Leu
Coding: c.1838C>T
MANE Select: NM_005632
dbSNP: rs374949685
Type: single nucleotide variant
Location: chr16:549467 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 613: the calpain catalytic domain; a UniProt-annotated variant site (in ogin; uncertain significance)

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

Disease context

CAPN15-related disorder

Also linked: oculogastrointestinal-neurodevelopmental syndrome

Similar variants

CAPN15 p.Arg867Cys Uncertain significance ★★ ⚠ same condition
CAPN15 p.Cys363Arg Uncertain significance ★★ ⚠ same condition
CAPN15 p.Glu776Ala Uncertain significance ★★ ⚠ same condition
CAPN15 p.Val841Met Uncertain significance ★★ ⚠ same condition
CAPN15 p.Glu210Ter Likely pathogenic ★ same condition
CAPN15 p.Gly653Ser Likely pathogenic ★ same condition
CAPN15 p.Arg446Trp Uncertain significance ★ ⚠ same condition
CAPN15 p.Arg482Gly Uncertain significance ★ ⚠ same condition

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-ser613leu (accessed [today's date]).

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