Is CASP8 p.Lys351Arg (c.1052A>G) pathogenic?

CASP8 p.Lys351Arg (c.1052A>G) is classified Uncertain significance in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-22). AlphaMissense: ambiguous (0.4402); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with CASP8 p.Lys351Arg (c.1052A>G)?

CASP8 p.Lys351Arg (c.1052A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CASP8 p.Lys351Arg (c.1052A>G) in the general population?

CASP8 p.Lys351Arg (c.1052A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CASP8 p.Lys351Arg (c.1052A>G)?

AlphaMissense predicts ambiguous (score 0.4402) — an in-silico prediction, not a clinical call.

CASP8 p.Lys351Arg

c.1052A>G · rs1949490941 · VCV3137624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4402 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4402	ambiguous
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -10.93	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 20 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,028 alleles

Overall 6.84e-05% 1/1,461,890 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.Lys351Arg
Coding: c.1052A>G
MANE Select: NM_001372051
dbSNP: rs1949490941
Type: single nucleotide variant
Location: chr2:201285065 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 351: a β-strand

Full CASP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASP8 c.306-1926A>G Uncertain significance ★★ same condition
CASP8 c.306-1935G>A Uncertain significance ★★ same condition
CASP8 p.Arg233Trp Uncertain significance ★★ ⚠ same condition
CASP8 p.Asp223Asn Uncertain significance ★★ ⚠ same condition
CASP8 p.Cys236Arg Uncertain significance ★★ ⚠ same condition
CASP8 p.Glu84Gly Uncertain significance ★★ ⚠ same condition
CASP8 p.Gly350Arg Uncertain significance ★★ ⚠ same condition
CASP8 p.Lys23Arg 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-lys351arg (accessed [today's date]).

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