Is PTGS2 p.Arg228Ser (c.682C>A) pathogenic?

PTGS2 p.Arg228Ser (c.682C>A) is classified Uncertain significance in PTGS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.2157); Ultra-rare (popmax 0.0294%, afr).

How common is PTGS2 p.Arg228Ser (c.682C>A) in the general population?

PTGS2 p.Arg228Ser (c.682C>A) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about PTGS2 p.Arg228Ser (c.682C>A)?

AlphaMissense predicts likely benign (score 0.2157) — an in-silico prediction, not a clinical call.

PTGS2 p.Arg228Ser

c.682C>A · VCV3940247

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2157	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,615 bp · p 0.079 · regional, not allelic
Overall
CADD	22.6	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 0.0294% African / African-American · 22/74,786 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.00155% 25/1,609,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,399
Remaining individualsnot grpmax-eligible	0.00161%	62,242
European (non-Finnish)	0.00017%	589,317

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: PTGS2
Protein: p.Arg228Ser
Coding: c.682C>A
MANE Select: NM_000963
Type: single nucleotide variant
Location: chr1:186676874 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.37 · 7 PDB
Residue 228: a UniProt-annotated variant site (in); an α-helix

Full PTGS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTGS2 p.Arg585= Benign ★★ same type
PTGS2 p.Asp300= Benign ★★ same type
PTGS2 p.His403= Benign ★★ same type
PTGS2 p.Ala436Ser Uncertain significance ★ ⚠ same type
PTGS2 p.Ala475Thr Uncertain significance ★ ⚠ same type
PTGS2 p.Ala529Ser Uncertain significance ★ ⚠ same type
PTGS2 p.Ala529Val Uncertain significance ★ ⚠ same type
PTGS2 p.Ala581Gly 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/ptgs2-p-arg228ser (accessed [today's date]).

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