Is CASP2 p.Arg417Gln (c.1250G>A) pathogenic?

CASP2 p.Arg417Gln (c.1250G>A) is classified Uncertain significance in CASP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: ambiguous (0.3851); Very rare (popmax 0.00223%, eas).

How common is CASP2 p.Arg417Gln (c.1250G>A) in the general population?

CASP2 p.Arg417Gln (c.1250G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CASP2 p.Arg417Gln (c.1250G>A)?

AlphaMissense predicts ambiguous (score 0.3851) — an in-silico prediction, not a clinical call.

CASP2 p.Arg417Gln

c.1250G>A · rs988986180 · VCV2547794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3851	ambiguous
REVEL	0.271	benign-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 3.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 13 kb · p 0.00043 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,896 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000496% 8/1,614,062 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
Admixed American	0.00167%	59,998
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,916
European (non-Finnish)	0.000339%	295,012

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: CASP2
Protein: p.Arg417Gln
Coding: c.1250G>A
MANE Select: NM_032982
dbSNP: rs988986180
Type: single nucleotide variant
Location: chr7:143304962 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.95 · 17 PDB
Residue 417: a UniProt-annotated variant site (in mrt80; likely pathogenic)

Full CASP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP2 p.Gln331Glu Uncertain significance ★★ ⚠ same type
CASP2 p.Ala412= Likely benign ★★ same type
CASP2 p.Gly7= Likely benign ★★ same type
CASP2 p.Ile387= Benign/Likely benign ★★ same type
CASP2 p.Lys254= Benign/Likely benign ★★ same type
CASP2 p.Thr267= Benign/Likely benign ★★ same type
CASP2 p.Tyr151= Benign ★★ same type
CASP2 p.Val29= 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/casp2-p-arg417gln (accessed [today's date]).

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