Is CASP8 p.Val450fs (c.1349_1352del) pathogenic?

CASP8 p.Val450fs (c.13491352del) is classified Uncertain significance in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). Very rare (popmax 0.00017%, nfe); Associated with autoimmune lymphoproliferative syndrome type 2B.

What condition is associated with CASP8 p.Val450fs (c.1349_1352del)?

CASP8 p.Val450fs (c.1349_1352del) is associated with autoimmune lymphoproliferative syndrome type 2B (ClinVar).

How common is CASP8 p.Val450fs (c.1349_1352del) in the general population?

CASP8 p.Val450fs (c.1349_1352del) is very rare (popmax 0.00017%, nfe) (gnomAD).

CASP8 p.Val450fs

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.1349_1352del · rs2470516855 · VCV2151955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

autoimmune lymphoproliferative syndrome type 2B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.4	GERP -0.14, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,460,742 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)grpmax	0.00017%	589,515

Remaining individuals 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.Val450fs
Coding: c.1349_1352del
MANE Select: NM_001372051
dbSNP: rs2470516855
Type: Deletion
Location: chr2:201286500 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 450: 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 c.306-1976del Pathogenic ★ same condition
CASP8 p.Asn306fs Pathogenic ★ same condition
CASP8 c.306-1981del Conflicting classifications of pathogenicity ★ same condition
CASP8 p.Val446fs Uncertain significance ★ same condition
CASP8 c.1304+9_1304+96del Likely benign ★ same condition
CASP8 c.305+14_305+19del Likely benign ★ same condition
CASP8 c.305+16del Likely benign ★ same condition
CASP8 c.306-1898_306-1897del Likely benign ★ 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-val450fs (accessed [today's date]).

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