Is CASP8 p.Arg435Gln (c.1304G>A) pathogenic?

CASP8 p.Arg435Gln (c.1304G>A) is classified Uncertain significance in CASP8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0885); Very rare (popmax 0.00223%, eas); Associated with autoimmune lymphoproliferative syndrome type 2B.

What condition is associated with CASP8 p.Arg435Gln (c.1304G>A)?

CASP8 p.Arg435Gln (c.1304G>A) is associated with autoimmune lymphoproliferative syndrome type 2B (ClinVar).

How common is CASP8 p.Arg435Gln (c.1304G>A) in the general population?

CASP8 p.Arg435Gln (c.1304G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CASP8 p.Arg435Gln (c.1304G>A)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

CASP8 p.Arg435Gln

Q: How is Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1304G>A · rs746401108 · VCV2155033

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune lymphoproliferative syndrome type 2B

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.42	donor loss · deltas
Constraint at this position
Conservation	phyloP 1.2	GERP -0.89, phastCons 0.99
Regional constraint	o/e 0.82	unconstrained · MANE · 20 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	20.5	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 0.00223% East Asian · 1/44,898 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000868% 14/1,612,854 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00626%	15,983
East Asiangrpmax	0.00223%	44,898
South Asian	0.0011%	91,032
European (non-Finnish)	0.000678%	147,502

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg435Gln
Coding: c.1304G>A
MANE Select: NM_001372051
dbSNP: rs746401108
Type: single nucleotide variant
Location: chr2:201285317 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 435: an α-helix

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

Disease context

autoimmune lymphoproliferative syndrome type 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

CASP8 p.Arg435Ter Pathogenic 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
CASP8 p.Ala96Ser 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-arg435gln (accessed [today's date]).

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