Is CAPN15 p.Ser720Phe (c.2159C>T) pathogenic?

CAPN15 p.Ser720Phe (c.2159C>T) is classified Pathogenic in CAPN15 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-05-07). AlphaMissense: likely pathogenic (0.9994); Very rare (popmax 8.48e-05%, nfe); Associated with oculogastrointestinal-neurodevelopmental syndrome.

What condition is associated with CAPN15 p.Ser720Phe (c.2159C>T)?

CAPN15 p.Ser720Phe (c.2159C>T) is associated with oculogastrointestinal-neurodevelopmental syndrome (ClinVar).

How common is CAPN15 p.Ser720Phe (c.2159C>T) in the general population?

CAPN15 p.Ser720Phe (c.2159C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CAPN15 p.Ser720Phe (c.2159C>T)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

CAPN15 p.Ser720Phe

c.2159C>T · rs2142072159 · VCV1074290

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

oculogastrointestinal-neurodevelopmental syndrome

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 2% in CAPN15
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -16.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,055 bp · p 0.036 · regional, not allelic
Overall
CADD	28.2	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 8.48e-05% European (non-Finnish) · 1/1,178,706 alleles

Overall 6.86e-05% 1/1,458,206 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.Ser720Phe
Coding: c.2159C>T
MANE Select: NM_005632
dbSNP: rs2142072159
Type: single nucleotide variant
Location: chr16:551394 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 720: 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

oculogastrointestinal-neurodevelopmental syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-ser720phe (accessed [today's date]).

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