Is CASP9 p.Arg173His (c.518G>A) pathogenic?

CASP9 p.Arg173His (c.518G>A) is classified Benign in CASP9 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-01). AlphaMissense: likely benign (0.0692); Low-frequency (popmax 1.35%, nfe).

How common is CASP9 p.Arg173His (c.518G>A) in the general population?

CASP9 p.Arg173His (c.518G>A) is low-frequency (popmax 1.35%, nfe) (gnomAD).

What do computational predictors say about CASP9 p.Arg173His (c.518G>A)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

CASP9 p.Arg173His

c.518G>A · rs2308950 · VCV3041435

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.35%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8	GERP -5.2
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	0.005	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 1.35% European (non-Finnish) · 15,934/1,180,018 alleles

Filtering AF 1.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.33%

Overall 1.22% 19,674/1,614,178 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.45%	29
European (non-Finnish)grpmax	1.35%	74
Remaining individualsnot grpmax-eligible	0.989%	101
Admixed American	0.721%	139
Ashkenazi Jewishnot grpmax-eligible	0.581%	172
African / African-American	0.232%	431
Middle Eastern	0.165%	606
South Asian	0.134%	747

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CASP9
Protein: p.Arg173His
Coding: c.518G>A
MANE Select: NM_001229
dbSNP: rs2308950
Type: single nucleotide variant
Location: chr1:15507011 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB
Residue 173: a UniProt-annotated variant site (in); an α-helix

Full CASP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP9 c.720+9C>T Benign ★★ same type
CASP9 p.Ala28Val Benign ★★ same type
CASP9 p.Thr366Asn Benign ★★ ⚠ same type
CASP9 p.Ala141Val Uncertain significance ★ ⚠ same type
CASP9 p.Ala215Thr Uncertain significance ★ ⚠ same type
CASP9 p.Ala220Val Uncertain significance ★ ⚠ same type
CASP9 p.Ala226Ser Uncertain significance ★ ⚠ same type
CASP9 p.Ala28Thr 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/casp9-p-arg173his (accessed [today's date]).

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