Is CAPN12 p.Phe139Val (c.415T>G) pathogenic?

CAPN12 p.Phe139Val (c.415T>G) is classified Uncertain significance in CAPN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: likely pathogenic (0.802); Absent from gnomAD v4.1; Associated with CAPN12-related disorder.

What condition is associated with CAPN12 p.Phe139Val (c.415T>G)?

CAPN12 p.Phe139Val (c.415T>G) is associated with CAPN12-related disorder (ClinVar).

How common is CAPN12 p.Phe139Val (c.415T>G) in the general population?

CAPN12 p.Phe139Val (c.415T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN12 p.Phe139Val (c.415T>G)?

AlphaMissense predicts likely pathogenic (score 0.802) — an in-silico prediction, not a clinical call.

CAPN12 p.Phe139Val

c.415T>G · rs757740657 · VCV2631361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.802 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CAPN12-related disorder

Computational evidence

Protein change
AlphaMissense	0.802	likely pathogenic
REVEL	0.568	indeterminate
SaProt	LLR -11.90	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 9.1	GERP 2.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPN12
Protein: p.Phe139Val
Coding: c.415T>G
MANE Select: NM_144691
dbSNP: rs757740657
Type: single nucleotide variant
Location: chr19:38742421 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 139: the calpain catalytic domain

Full CAPN12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CAPN12-related disorder

Similar variants

CAPN12 c.1627-6C>A Uncertain significance ★ same condition
CAPN12 p.Gln626Ter Uncertain significance ★ same condition
CAPN12 p.Trp363Arg Uncertain significance ⚠ same condition
CAPN12 c.1583+9C>T Likely benign same condition
CAPN12 c.1879-3C>T Likely benign same condition
CAPN12 c.561-7C>T Likely benign same condition
CAPN12 p.Ala110= Benign same condition
CAPN12 p.Ala409= Likely benign 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/capn12-p-phe139val (accessed [today's date]).

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