Is PTGES2 p.Arg235Gln (c.704G>A) pathogenic?

PTGES2 p.Arg235Gln (c.704G>A) is classified Uncertain significance in PTGES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.8138); Very rare (popmax 0.00668%, eas).

How common is PTGES2 p.Arg235Gln (c.704G>A) in the general population?

PTGES2 p.Arg235Gln (c.704G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about PTGES2 p.Arg235Gln (c.704G>A)?

AlphaMissense predicts likely pathogenic (score 0.8138) — an in-silico prediction, not a clinical call.

PTGES2 p.Arg235Gln

c.704G>A · VCV3940176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8138	likely pathogenic
REVEL	0.594	indeterminate
SaProt	LLR -14.00	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 4.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,569 bp · p 0.85 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00668% East Asian · 3/44,878 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000559% 9/1,610,682 alleles · very rare exomes 9/1,458,394 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,959
Admixed American	0.00167%	60,020
Finnishnot grpmax-eligible	0.00165%	60,650
African / African-American	0.00133%	75,036
European (non-Finnish)	0.000254%	393,335

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: PTGES2
Protein: p.Arg235Gln
Coding: c.704G>A
MANE Select: NM_025072
Type: single nucleotide variant
Location: chr9:128123117 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.07

Full PTGES2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTGES2 p.Lys269Asn Benign ★★ same type
PTGES2 p.Ala10Gly Uncertain significance ★ ⚠ same type
PTGES2 p.Ala171Ser Uncertain significance ★ ⚠ same type
PTGES2 p.Ala238Val Uncertain significance ★ ⚠ same type
PTGES2 p.Ala259Val Uncertain significance ★ ⚠ same type
PTGES2 p.Ala284Val Uncertain significance ★ ⚠ same type
PTGES2 p.Arg117Gln Uncertain significance ★ ⚠ same type
PTGES2 p.Arg136His 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/ptges2-p-arg235gln (accessed [today's date]).

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