Is CASP4 p.Val30Met (c.88G>A) pathogenic?

CASP4 p.Val30Met (c.88G>A) is classified Uncertain significance in CASP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.1767); Rare (popmax 0.689%, afr).

How common is CASP4 p.Val30Met (c.88G>A) in the general population?

CASP4 p.Val30Met (c.88G>A) is rare (popmax 0.689%, afr) (gnomAD).

What do computational predictors say about CASP4 p.Val30Met (c.88G>A)?

AlphaMissense predicts likely benign (score 0.1767) — an in-silico prediction, not a clinical call.

CASP4 p.Val30Met

c.88G>A · VCV4219390

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1767 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.689%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1767	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -7.24	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 -2.3	GERP 0.66
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.53 · regional, not allelic
Overall
CADD	7.045	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.689% African / African-American · 517/74,992 alleles

Filtering AF 0.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.621%

Overall 0.0429% 693/1,613,694 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.689%	145
Middle Eastern	0.38%	263
Remaining individualsnot grpmax-eligible	0.088%	1,136
Admixed American	0.0701%	1,427
European (non-Finnish)	0.00466%	21,451
South Asian	0.0011%	91,068

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: CASP4
Protein: p.Val30Met
Coding: c.88G>A
MANE Select: NM_001225
Type: single nucleotide variant
Location: chr11:104954921 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.00 · 11 PDB
Residue 30: the card domain; the 'required for lps-binding' region

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-val30met (accessed [today's date]).

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