Is CASP8AP2 p.Ala617Pro (c.1849G>C) pathogenic?

CASP8AP2 p.Ala617Pro (c.1849G>C) is classified Uncertain significance in CASP8AP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). Very rare (popmax 0.00149%, afr).

How common is CASP8AP2 p.Ala617Pro (c.1849G>C) in the general population?

CASP8AP2 p.Ala617Pro (c.1849G>C) is very rare (popmax 0.00149%, afr) (gnomAD).

CASP8AP2 p.Ala617Pro

c.1849G>C · VCV4219443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00149%, afr)

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 -0.61	GERP -0.29, phastCons 0.001
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 7.8e-31 · regional, not allelic
Overall
CADD	5.915	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00149% African / African-American · 1/67,230 alleles

Overall 0.000657% 1/152,206 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: CASP8AP2
Protein: p.Ala617Pro
Coding: c.1849G>C
MANE Select: NM_001137667
Type: single nucleotide variant
Location: chr6:89863558 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 44.28 · 4 PDB

Full CASP8AP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP8AP2 p.Ala1030Ser Uncertain significance ★ same type
CASP8AP2 p.Ala1518Asp Uncertain significance ★ same type
CASP8AP2 p.Ala1731Thr Uncertain significance ★ same type
CASP8AP2 p.Ala1748Asp Uncertain significance ★ same type
CASP8AP2 p.Ala1779Gly Uncertain significance ★ same type
CASP8AP2 p.Ala1884Val Uncertain significance ★ same type
CASP8AP2 p.Ala19Gly Uncertain significance ★ same type
CASP8AP2 p.Ala453Val Uncertain significance ★ 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/casp8ap2-p-ala617pro (accessed [today's date]).

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