Is CAPS2 p.Phe316Leu (c.946T>C) pathogenic?

CAPS2 p.Phe316Leu (c.946T>C) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely pathogenic (0.9337); Very rare (popmax 0.00133%, afr).

How common is CAPS2 p.Phe316Leu (c.946T>C) in the general population?

CAPS2 p.Phe316Leu (c.946T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CAPS2 p.Phe316Leu (c.946T>C)?

AlphaMissense predicts likely pathogenic (score 0.9337) — an in-silico prediction, not a clinical call.

CAPS2 p.Phe316Leu

c.946T>C · rs1036605674 · VCV3137248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
AlphaMissense	0.9337	likely pathogenic
REVEL	0.445	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Overall
CADD	25.5	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 F373L vs ClinVar F316L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,956 alleles

Overall 6.85e-05% 1/1,458,888 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: CAPS2
Protein: p.Phe316Leu
Coding: c.946T>C
MANE Select: NM_017954 · reported on NM_001355024
dbSNP: rs1036605674
Type: single nucleotide variant
Location: chr12:75293352 (GRCh38)
Structure: AlphaFold pLDDT 79.91
Residue 316: the dm10 domain

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

Similar variants

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
CADPS2 p.Thr819= 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-phe316leu (accessed [today's date]).

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