Is CAPS2 p.Leu417Ile (c.1249C>A) pathogenic?

CAPS2 p.Leu417Ile (c.1249C>A) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1734); Absent from gnomAD v4.1.

How common is CAPS2 p.Leu417Ile (c.1249C>A) in the general population?

CAPS2 p.Leu417Ile (c.1249C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPS2 p.Leu417Ile (c.1249C>A)?

AlphaMissense predicts likely benign (score 0.1734) — an in-silico prediction, not a clinical call.

CAPS2 p.Leu417Ile

c.1249C>A · VCV4219009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1734 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1734	likely benign
REVEL	0.475	indeterminate
SaProt	LLR -10.63	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.014, phastCons 1
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L474I vs ClinVar L417I) — verify the residue.

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: CAPS2
Protein: p.Leu417Ile
Coding: c.1249C>A
MANE Select: NM_017954 · reported on NM_001355024
Type: single nucleotide variant
Location: chr12:75289653 (GRCh38)
Structure: AlphaFold pLDDT 79.91
Residue 417: the c2 domain

Full CAPS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CADPS2 p.Thr417Ile Uncertain significance ★ ⚠ same residue
CADPS2 c.3718-15A>C Benign ★★ same type
CADPS2 p.Ala298Thr Benign ★★ same type
CADPS2 p.Asp1088Asn Likely benign ★★ same type
CADPS2 p.Glu1010Lys Benign ★★ same type
CADPS2 p.Leu154= Likely benign ★★ same type
CADPS2 p.Lys338= Benign ★★ same type
CADPS2 p.Met828Val Benign ★★ ⚠ 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/caps2-p-leu417ile (accessed [today's date]).

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