Is CAPS2 p.Leu267Phe (c.799C>T) pathogenic?

CAPS2 p.Leu267Phe (c.799C>T) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: ambiguous (0.3848); Very rare (popmax 0.00168%, amr).

How common is CAPS2 p.Leu267Phe (c.799C>T) in the general population?

CAPS2 p.Leu267Phe (c.799C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about CAPS2 p.Leu267Phe (c.799C>T)?

AlphaMissense predicts ambiguous (score 0.3848) — an in-silico prediction, not a clinical call.

CAPS2 p.Leu267Phe

c.799C>T · rs1032743770 · VCV3137254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Computational evidence

Protein change
AlphaMissense	0.3848	ambiguous
REVEL	0.197	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.5	GERP 1.5, phastCons 1
Overall
CADD	24.1	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 L324F vs ClinVar L267F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,672 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000682% 11/1,611,746 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,672
European (non-Finnish)	0.000848%	117,908

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.Leu267Phe
Coding: c.799C>T
MANE Select: NM_017954 · reported on NM_001355024
dbSNP: rs1032743770
Type: single nucleotide variant
Location: chr12:75298908 (GRCh38)
Structure: AlphaFold pLDDT 79.91

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-leu267phe (accessed [today's date]).

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