Is CASP8 p.Val410fs (c.1228_1229del) pathogenic?

CASP8 p.Val410fs (c.12281229del) is classified Pathogenic in CASP8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2005-01-06). Very rare (popmax 0.000593%, nfe); Associated with hepatocellular carcinoma.

What condition is associated with CASP8 p.Val410fs (c.1228_1229del)?

CASP8 p.Val410fs (c.1228_1229del) is associated with hepatocellular carcinoma (ClinVar).

How common is CASP8 p.Val410fs (c.1228_1229del) in the general population?

CASP8 p.Val410fs (c.1228_1229del) is very rare (popmax 0.000593%, nfe) (gnomAD).

CASP8 p.Val410fs

c.1228_1229del · rs587776665 · VCV7761

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

hepatocellular carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.46	GERP 0.97, phastCons 0.033
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,050 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,112 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.Val410fs
Coding: c.1228_1229del
MANE Select: NM_001372051
dbSNP: rs587776665
Type: Microsatellite
Location: chr2:201285238 (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

hepatocellular carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASP8 p.Ser113= Benign/Likely benign ★★ same condition
CASP8 c.306-1954_306-1953del Pathogenic ★ same type
CASP8 p.Ala165fs Pathogenic ★ same type
CASP8 p.Glu111del Uncertain significance ★ same type
CASP8 c.*17GTTTT[5] Likely benign ★ same type

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-val410fs (accessed [today's date]).

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