Is CASP8 p.Lys320= (c.960G>A) pathogenic?

CASP8 p.Lys320= (c.960G>A) is classified Benign in CASP8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 25.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with autoimmune lymphoproliferative syndrome type 2B.

What condition is associated with CASP8 p.Lys320= (c.960G>A)?

CASP8 p.Lys320= (c.960G>A) is associated with autoimmune lymphoproliferative syndrome type 2B (ClinVar).

CASP8 p.Lys320=

Q: How common is CASP8 p.Lys320= (c.960G>A) in the general population?

CASP8 p.Lys320= (c.960G>A) is common (popmax 25.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.960G>A · rs1045487 · VCV333505

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 25.2%, sas) — too common for a highly-penetrant pathogenic allele

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 0.38	GERP -0.8, phastCons 0.72
Overall
CADD	5.984	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 25.2% South Asian · 22,933/91,066 alleles

Filtering AF 24.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.8%

Overall 7.25% 117,025/1,613,906 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	25.2%	4
East Asian	22.3%	4
African / African-American	21.4%	5
Middle Eastern	14.9%	7
Ashkenazi Jewishnot grpmax-eligible	8.43%	12
Remaining individualsnot grpmax-eligible	8.33%	12
Amishnot grpmax-eligible	6.58%	15
European (non-Finnish)	4.62%	22
Finnishnot grpmax-eligible	4.06%	25
Admixed American	3.69%	27

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.Lys320=
Coding: c.960G>A
MANE Select: NM_001372051
dbSNP: rs1045487
Type: single nucleotide variant
Location: chr2:201284973 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB

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.Lys320Thr Uncertain significance ★ ⚠ 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-lys320 (accessed [today's date]).

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