Is CAPN14 p.Ser393Phe (c.1178C>T) pathogenic?

CAPN14 p.Ser393Phe (c.1178C>T) is classified Uncertain significance in CAPN14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0889); Ultra-rare (popmax 0.0109%, afr).

How common is CAPN14 p.Ser393Phe (c.1178C>T) in the general population?

CAPN14 p.Ser393Phe (c.1178C>T) is ultra-rare (popmax 0.0109%, afr) (gnomAD).

What do computational predictors say about CAPN14 p.Ser393Phe (c.1178C>T)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

CAPN14 p.Ser393Phe

c.1178C>T · VCV3995182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.79, phastCons 0.002
Regional constraint	o/e 1.01	unconstrained · MANE · 31 kb · p 0.76 · regional, not allelic
Overall
CADD	12.86	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0109% African / African-American · 8/73,172 alleles

Filtering AF 0.00539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.000967% 15/1,551,584 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0109%	9,147
Admixed American	0.00784%	12,748
Remaining individualsnot grpmax-eligible	0.00499%	20,037

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: CAPN14
Protein: p.Ser393Phe
Coding: c.1178C>T
MANE Select: NM_001145122
Type: single nucleotide variant
Location: chr2:31192035 (GRCh38)
Gene constraint: LOEUF 1.109 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.02
Residue 393: the 'domain iii' region

Full CAPN14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN14 p.Leu185= Benign ★★ same type
CAPN14 p.Ala183Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala255Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala35Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala51Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala613Val Uncertain significance ★ ⚠ same type
CAPN14 p.Arg119Gln Uncertain significance ★ ⚠ same type
CAPN14 p.Arg119Trp 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/capn14-p-ser393phe (accessed [today's date]).

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