Is CASP8 p.His304= (c.912C>T) pathogenic?

CASP8 p.His304= (c.912C>T) is classified Likely benign in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). Very rare (popmax 0.00559%, nfe); Associated with autoimmune lymphoproliferative syndrome type 2B.

What condition is associated with CASP8 p.His304= (c.912C>T)?

CASP8 p.His304= (c.912C>T) is associated with autoimmune lymphoproliferative syndrome type 2B (ClinVar).

How common is CASP8 p.His304= (c.912C>T) in the general population?

CASP8 p.His304= (c.912C>T) is very rare (popmax 0.00559%, nfe) (gnomAD).

CASP8 p.His304=

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.912C>T · rs139361998 · VCV2173369

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00559%, 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 -0.23	GERP -0.17
Overall
CADD	6.708	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00559% European (non-Finnish) · 66/1,180,036 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00489% 79/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,147
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)grpmax	0.00559%	17,879
African / African-American	0.00134%	74,880

Finnish 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.His304=
Coding: c.912C>T
MANE Select: NM_001372051
dbSNP: rs139361998
Type: single nucleotide variant
Location: chr2:201284925 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 304: 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-his304 (accessed [today's date]).

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