Is CASP8 p.Glu449Asp (c.1347A>C) pathogenic?

CASP8 p.Glu449Asp (c.1347A>C) is classified Uncertain significance in CASP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.219); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CASP8 p.Glu449Asp (c.1347A>C)?

CASP8 p.Glu449Asp (c.1347A>C) is associated with Inborn genetic diseases (ClinVar).

How common is CASP8 p.Glu449Asp (c.1347A>C) in the general population?

CASP8 p.Glu449Asp (c.1347A>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CASP8 p.Glu449Asp (c.1347A>C)?

AlphaMissense predicts likely benign (score 0.219) — an in-silico prediction, not a clinical call.

CASP8 p.Glu449Asp

c.1347A>C · VCV3995646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.219	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.11	GERP -2.1, phastCons 0.01
Regional constraint	o/e 0.82	unconstrained · MANE · 20 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	13.75	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Overall 6.85e-05% 1/1,460,714 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.Glu449Asp
Coding: c.1347A>C
MANE Select: NM_001372051
Type: single nucleotide variant
Location: chr2:201286501 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 36 PDB
Residue 449: an α-helix

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-glu449asp (accessed [today's date]).

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