Is CAPN15 p.Ser8Phe (c.23C>T) pathogenic?

CAPN15 p.Ser8Phe (c.23C>T) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.3469); Very rare (popmax 0.0011%, sas).

How common is CAPN15 p.Ser8Phe (c.23C>T) in the general population?

CAPN15 p.Ser8Phe (c.23C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CAPN15 p.Ser8Phe (c.23C>T)?

AlphaMissense predicts ambiguous (score 0.3469) — an in-silico prediction, not a clinical call.

CAPN15 p.Ser8Phe

c.23C>T · VCV3995220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3469 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3469	ambiguous
REVEL	0.244	benign-leaning
SaProt	LLR -11.82	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.24, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 2,296 bp · p 0.00013 · regional, not allelic
Overall
CADD	26.4	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 0.0011% South Asian · 1/90,832 alleles

Overall 6.86e-05% 1/1,458,256 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.Ser8Phe
Coding: c.23C>T
MANE Select: NM_005632
Type: single nucleotide variant
Location: chr16:546861 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65

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

Similar variants

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
CAPN15 p.Val489Met Uncertain significance ★★ ⚠ same type
CAPN15 p.Val841Met 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-ser8phe (accessed [today's date]).

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