Is CASP8 p.Lys250Arg (c.749A>G) pathogenic?

CASP8 p.Lys250Arg (c.749A>G) is classified Uncertain significance in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-12). AlphaMissense: likely benign (0.0735); Very rare (popmax 0.000678%, nfe); Associated with autoimmune lymphoproliferative syndrome type 2B.

What condition is associated with CASP8 p.Lys250Arg (c.749A>G)?

CASP8 p.Lys250Arg (c.749A>G) is associated with autoimmune lymphoproliferative syndrome type 2B (ClinVar).

How common is CASP8 p.Lys250Arg (c.749A>G) in the general population?

CASP8 p.Lys250Arg (c.749A>G) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CASP8 p.Lys250Arg (c.749A>G)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

CASP8 p.Lys250Arg

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.749A>G · rs775747472 · VCV2120767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune lymphoproliferative syndrome type 2B

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -6.70	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 0.33	GERP -2.4
Regional constraint	o/e 0.82	unconstrained · MANE · 20 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	2.778	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 0.000678% European (non-Finnish) · 8/1,179,982 alleles

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

Overall 0.000547% 8/1,461,810 alleles · very rare

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.Lys250Arg
Coding: c.749A>G
MANE Select: NM_001372051
dbSNP: rs775747472
Type: single nucleotide variant
Location: chr2:201276915 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 250: 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.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
CASP8 p.Arg233Trp 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-lys250arg (accessed [today's date]).

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