Is CASP8 p.Arg233Trp (c.697C>T) pathogenic?

CASP8 p.Arg233Trp (c.697C>T) is classified Uncertain significance in CASP8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-18). AlphaMissense: likely pathogenic (0.6041); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with CASP8 p.Arg233Trp (c.697C>T)?

CASP8 p.Arg233Trp (c.697C>T) is associated with Inborn genetic diseases, autoimmune lymphoproliferative syndrome type 2B (ClinVar).

How common is CASP8 p.Arg233Trp (c.697C>T) in the general population?

CASP8 p.Arg233Trp (c.697C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CASP8 p.Arg233Trp (c.697C>T)?

AlphaMissense predicts likely pathogenic (score 0.6041) — an in-silico prediction, not a clinical call.

CASP8 p.Arg233Trp

c.697C>T · rs760898260 · VCV1435155

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6041 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6041	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -12.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	acceptor loss, 36 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 20 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,862 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000744% 12/1,613,842 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,431
South Asian	0.0022%	45,536
European (non-Finnish)	0.000678%	147,495

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: CASP8
Protein: p.Arg233Trp
Coding: c.697C>T
MANE Select: NM_001372051
dbSNP: rs760898260
Type: single nucleotide variant
Location: chr2:201276863 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB

Full CASP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoimmune lymphoproliferative syndrome type 2B

Similar variants

CASP8 p.Arg233Gln Uncertain significance ★ ⚠ same residue
CASP8 p.Arg233Gly Uncertain significance ★ ⚠ same residue
CASP8 p.Arg248Trp Pathogenic/Likely pathogenic ★★ same condition
CASP8 c.306-1926A>G Uncertain significance ★★ same condition
CASP8 c.306-1935G>A Uncertain significance ★★ same condition
CASP8 c.306-1971A>G Uncertain significance ★★ same condition
CASP8 c.660+6C>T Uncertain significance ★★ same condition
CASP8 c.*107C>T Uncertain significance ★★ same condition

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/casp8-p-arg233trp (accessed [today's date]).

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