Is CAPS2 p.Val45Phe (c.133G>T) pathogenic?

CAPS2 p.Val45Phe (c.133G>T) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-21). AlphaMissense: ambiguous (0.3716); Rare (popmax 0.116%, eas).

How common is CAPS2 p.Val45Phe (c.133G>T) in the general population?

CAPS2 p.Val45Phe (c.133G>T) is rare (popmax 0.116%, eas) (gnomAD).

What do computational predictors say about CAPS2 p.Val45Phe (c.133G>T)?

AlphaMissense predicts ambiguous (score 0.3716) — an in-silico prediction, not a clinical call.

CAPS2 p.Val45Phe

c.133G>T · rs978553355 · VCV2594288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3716 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, eas)

Computational evidence

Protein change
AlphaMissense	0.3716	ambiguous
REVEL	0.15	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.3, 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 V64F vs ClinVar V45F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.116% East Asian · 47/40,690 alleles

Filtering AF 0.0892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0799%

Overall 0.00324% 50/1,542,978 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.116%	866
Remaining individualsnot grpmax-eligible	0.00503%	19,869

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.Val45Phe
Coding: c.133G>T
MANE Select: NM_017954 · reported on NM_001355024
dbSNP: rs978553355
Type: single nucleotide variant
Location: chr12:75323221 (GRCh38)
Structure: AlphaFold pLDDT 79.91
Residue 45: the 'disordered' region

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

Similar variants

RNF133 p.Ser45Leu Uncertain significance ★ ⚠ same residue
RNF148 p.Thr45Ala 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

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-val45phe (accessed [today's date]).

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