Is CASP1 p.Val133Ala (c.398T>C) pathogenic?

CASP1 p.Val133Ala (c.398T>C) is classified Uncertain significance in CASP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). AlphaMissense: likely benign (0.3193); Very rare (popmax 0.0011%, sas).

How common is CASP1 p.Val133Ala (c.398T>C) in the general population?

CASP1 p.Val133Ala (c.398T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CASP1 p.Val133Ala (c.398T>C)?

AlphaMissense predicts likely benign (score 0.3193) — an in-silico prediction, not a clinical call.

CASP1 p.Val133Ala

c.398T>C · rs755154041 · VCV3137561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3193	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 8,852 bp · p 0.8 · regional, not allelic
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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,050 alleles

Overall 0.000137% 2/1,460,720 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,050
European (non-Finnish)	8.48e-05%	1,179,262

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: CASP1
Protein: p.Val133Ala
Coding: c.398T>C
MANE Select: NM_001257118
dbSNP: rs755154041
Type: single nucleotide variant
Location: chr11:105031220 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 82.48 · 42 PDB

Full CASP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP1 p.Arg143= Benign ★★ same type
CASP1 p.Ile328= Likely benign ★★ same type
CASP1 p.Lys37Gln Benign ★★ same type
CASP1 p.Ala141Gly Uncertain significance ★ ⚠ same type
CASP1 p.Ala141Thr Uncertain significance ★ ⚠ same type
CASP1 p.Ala217Ser Uncertain significance ★ ⚠ same type
CASP1 p.Ala84Ser Uncertain significance ★ ⚠ same type
CASP1 p.Arg15Cys Uncertain significance ★ ⚠ 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/casp1-p-val133ala (accessed [today's date]).

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