Is CAPS2 p.Leu283Phe (c.847C>T) pathogenic?

CAPS2 p.Leu283Phe (c.847C>T) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.329); Very rare (popmax 0.00534%, afr).

How common is CAPS2 p.Leu283Phe (c.847C>T) in the general population?

CAPS2 p.Leu283Phe (c.847C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CAPS2 p.Leu283Phe (c.847C>T)?

AlphaMissense predicts likely benign (score 0.329) — an in-silico prediction, not a clinical call.

CAPS2 p.Leu283Phe

c.847C>T · VCV4648222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Computational evidence

Protein change
AlphaMissense	0.329	likely benign
REVEL	0.301	indeterminate
Splicing
SpliceAI	Δ0.27	acceptor loss · deltas
Pangolin	Δ0.22	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Overall
CADD	24.5	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 L340F vs ClinVar L283F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,876 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00105% 17/1,612,948 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,719
European (non-Finnish)	0.0011%	90,703

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.Leu283Phe
Coding: c.847C>T
MANE Select: NM_017954 · reported on NM_001355024
Type: single nucleotide variant
Location: chr12:75298770 (GRCh38)
Structure: AlphaFold pLDDT 79.91

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

Similar variants

RNF133 p.Ile283Val 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-leu283phe (accessed [today's date]).

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