Is CAPN10 p.Phe14Leu (c.42C>G) pathogenic?

CAPN10 p.Phe14Leu (c.42C>G) is classified Uncertain significance in CAPN10 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). AlphaMissense: likely pathogenic (0.9394); Very rare (popmax 0.000269%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAPN10 p.Phe14Leu (c.42C>G)?

CAPN10 p.Phe14Leu (c.42C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN10 p.Phe14Leu (c.42C>G) in the general population?

CAPN10 p.Phe14Leu (c.42C>G) is very rare (popmax 0.000269%, nfe) (gnomAD).

What do computational predictors say about CAPN10 p.Phe14Leu (c.42C>G)?

AlphaMissense predicts likely pathogenic (score 0.9394) — an in-silico prediction, not a clinical call.

CAPN10 p.Phe14Leu

c.42C>G · VCV3263151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9394 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000269%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9394	likely pathogenic · top 7% in CAPN10
REVEL	0.294	indeterminate
SaProt	LLR -11.01	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 2.5	GERP 0.91, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.013 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000269% European (non-Finnish) · 3/1,115,308 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000226% 3/1,326,522 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: CAPN10
Protein: p.Phe14Leu
Coding: c.42C>G
MANE Select: NM_023083
Type: single nucleotide variant
Location: chr2:240586953 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.91
Residue 14: the calpain catalytic domain

Full CAPN10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAPN10 p.Arg127Cys Uncertain significance ★★ ⚠ same condition
CAPN10 p.Gly526Ser Uncertain significance ★★ ⚠ same condition
CAPN10 p.Pro46Ser Uncertain significance ★★ ⚠ same condition
CAPN10 p.Thr339Met Uncertain significance ★★ ⚠ same condition
CAPN10 p.Ala156Thr Uncertain significance ★ ⚠ same condition
CAPN10 p.Ala252Val Uncertain significance ★ ⚠ same condition
CAPN10 p.Ala341Thr Uncertain significance ★ ⚠ same condition
CAPN10 p.Ala389Val 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/capn10-p-phe14leu (accessed [today's date]).

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