Is CASP8 p.Lys121= (c.363G>A) pathogenic?

CASP8 p.Lys121= (c.363G>A) is classified Likely benign in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-12). Ultra-rare (popmax 0.012%, afr); Associated with autoimmune lymphoproliferative syndrome type 2B.

What condition is associated with CASP8 p.Lys121= (c.363G>A)?

CASP8 p.Lys121= (c.363G>A) is associated with autoimmune lymphoproliferative syndrome type 2B (ClinVar).

How common is CASP8 p.Lys121= (c.363G>A) in the general population?

CASP8 p.Lys121= (c.363G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

CASP8 p.Lys121=

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.363G>A · rs773845990 · VCV752529

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

autoimmune lymphoproliferative syndrome type 2B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.4, phastCons 1
Overall
CADD	3.884	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,904 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000931% 15/1,611,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,323
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,406
European (non-Finnish)	0.00034%	294,466

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.Lys121=
Coding: c.363G>A
MANE Select: NM_001372051
dbSNP: rs773845990
Type: single nucleotide variant
Location: chr2:201271573 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 121: the ded 2 domain; 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-lys121 (accessed [today's date]).

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