Is CAPNS2 p.Leu139Pro (c.416T>C) pathogenic?

CAPNS2 p.Leu139Pro (c.416T>C) is classified Uncertain significance in CAPNS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely pathogenic (0.9744); Absent from gnomAD v4.1.

How common is CAPNS2 p.Leu139Pro (c.416T>C) in the general population?

CAPNS2 p.Leu139Pro (c.416T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPNS2 p.Leu139Pro (c.416T>C)?

AlphaMissense predicts likely pathogenic (score 0.9744) — an in-silico prediction, not a clinical call.

CAPNS2 p.Leu139Pro

c.416T>C · VCV3484884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9744 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9744	likely pathogenic · top 4% in CAPNS2
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -15.98	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 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 743 bp · p 0.19 · regional, not allelic
Overall
CADD	29.5	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: CAPNS2
Protein: p.Leu139Pro
Coding: c.416T>C
MANE Select: NM_032330
Type: single nucleotide variant
Location: chr16:55567172 (GRCh38)
Gene constraint: LOEUF 1.114 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.67
Residue 139: the ef-hand 1 domain

Full CAPNS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPNS2 p.Ala18Val Uncertain significance ★ ⚠ same type
CAPNS2 p.Arg125Gln Uncertain significance ★ ⚠ same type
CAPNS2 p.Arg196Trp Uncertain significance ★ ⚠ same type
CAPNS2 p.Arg215His Uncertain significance ★ ⚠ same type
CAPNS2 p.Arg221His Uncertain significance ★ ⚠ same type
CAPNS2 p.Arg221Leu Uncertain significance ★ ⚠ same type
CAPNS2 p.Arg82Trp Uncertain significance ★ ⚠ same type
CAPNS2 p.Asp132Gly 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/capns2-p-leu139pro (accessed [today's date]).

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