Is CASP1 p.Val348Leu (c.1042G>C) pathogenic?

CASP1 p.Val348Leu (c.1042G>C) is classified Likely benign in CASP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1258); Very rare (popmax 0.00238%, nfe).

How common is CASP1 p.Val348Leu (c.1042G>C) in the general population?

CASP1 p.Val348Leu (c.1042G>C) is very rare (popmax 0.00238%, nfe) (gnomAD).

What do computational predictors say about CASP1 p.Val348Leu (c.1042G>C)?

AlphaMissense predicts likely benign (score 0.1258) — an in-silico prediction, not a clinical call.

CASP1 p.Val348Leu

c.1042G>C · VCV4219355

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00238%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1258	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.012	phastCons 0.01
Regional constraint	o/e 0.99	unconstrained · MANE · 8,852 bp · p 0.8 · regional, not allelic
Overall
CADD	0.179	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 0.00238% European (non-Finnish) · 28/1,174,796 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,608,004 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00238%	41,957
Admixed American	0.00167%	59,878

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.Val348Leu
Coding: c.1042G>C
MANE Select: NM_001257118
Type: single nucleotide variant
Location: chr11:105026916 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 82.48 · 42 PDB
Residue 348: an α-helix

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-val348leu (accessed [today's date]).

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