Is CASP8 p.Leu440= (c.1320C>G) pathogenic?

CASP8 p.Leu440= (c.1320C>G) is classified Likely benign in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). Very rare (popmax 0.00153%, nfe); Associated with autoimmune lymphoproliferative syndrome type 2B.

What condition is associated with CASP8 p.Leu440= (c.1320C>G)?

CASP8 p.Leu440= (c.1320C>G) is associated with autoimmune lymphoproliferative syndrome type 2B (ClinVar).

How common is CASP8 p.Leu440= (c.1320C>G) in the general population?

CASP8 p.Leu440= (c.1320C>G) is very rare (popmax 0.00153%, nfe) (gnomAD).

CASP8 p.Leu440=

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.1320C>G · VCV3624613

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

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 -1.2	GERP -3.7
Overall
CADD	2.939	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,178,542 alleles

Filtering AF 0.000955% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000788%

Overall 0.00112% 18/1,612,370 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.Leu440=
Coding: c.1320C>G
MANE Select: NM_001372051
Type: single nucleotide variant
Location: chr2:201286474 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 440: 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-leu440 (accessed [today's date]).

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