Is CASP4 p.Val346Ile (c.1036G>A) pathogenic?

CASP4 p.Val346Ile (c.1036G>A) is classified Uncertain significance in CASP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-06). AlphaMissense: likely benign (0.2122); Absent from gnomAD v4.1.

How common is CASP4 p.Val346Ile (c.1036G>A) in the general population?

CASP4 p.Val346Ile (c.1036G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASP4 p.Val346Ile (c.1036G>A)?

AlphaMissense predicts likely benign (score 0.2122) — an in-silico prediction, not a clinical call.

CASP4 p.Val346Ile

c.1036G>A · VCV3263429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2122 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2122	likely benign
REVEL	0.415	indeterminate
SaProt	LLR -10.22	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.6	GERP 0.85, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.53 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASP4
Protein: p.Val346Ile
Coding: c.1036G>A
MANE Select: NM_001225
Type: single nucleotide variant
Location: chr11:104944851 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.00 · 11 PDB
Residue 346: an α-helix

Full CASP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP4 p.Asp47Asn Benign ★★ same type
CASP4 p.Glu284Asp Benign ★★ same type
CASP4 p.Ala94Val Uncertain significance ★ ⚠ same type
CASP4 p.Arg116Gly Uncertain significance ★ ⚠ same type
CASP4 p.Arg136His Uncertain significance ★ ⚠ same type
CASP4 p.Arg136Ser Uncertain significance ★ ⚠ same type
CASP4 p.Arg259Ile Uncertain significance ★ ⚠ same type
CASP4 p.Arg263Cys 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/casp4-p-val346ile (accessed [today's date]).

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