Is CASP4 p.Arg66His (c.197G>A) pathogenic?

CASP4 p.Arg66His (c.197G>A) is classified Uncertain significance in CASP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-21). AlphaMissense: likely benign (0.0727); Ultra-rare (popmax 0.0751%, amr).

How common is CASP4 p.Arg66His (c.197G>A) in the general population?

CASP4 p.Arg66His (c.197G>A) is ultra-rare (popmax 0.0751%, amr) (gnomAD).

What do computational predictors say about CASP4 p.Arg66His (c.197G>A)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

CASP4 p.Arg66His

c.197G>A · rs150997782 · VCV2366093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0751%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -8.99	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 -3.1	GERP -3.4
Regional constraint	o/e 0.97	unconstrained · MANE · 24 kb · p 0.53 · regional, not allelic
Overall
CADD	2.995	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 0.0751% Admixed American · 45/59,958 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.0133% 214/1,613,596 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0751%	1,332
European (non-Finnish)	0.0136%	7,327
Remaining individualsnot grpmax-eligible	0.008%	12,496
African / African-American	0.004%	25,005

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.Arg66His
Coding: c.197G>A
MANE Select: NM_001225
dbSNP: rs150997782
Type: single nucleotide variant
Location: chr11:104954812 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.00 · 11 PDB
Residue 66: the card domain

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-arg66his (accessed [today's date]).

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