Is PTGS2 p.Lys355Glu (c.1063A>G) pathogenic?

PTGS2 p.Lys355Glu (c.1063A>G) is classified Uncertain significance in PTGS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0751); Very rare (popmax 0.00267%, afr).

How common is PTGS2 p.Lys355Glu (c.1063A>G) in the general population?

PTGS2 p.Lys355Glu (c.1063A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PTGS2 p.Lys355Glu (c.1063A>G)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

PTGS2 p.Lys355Glu

c.1063A>G · VCV4573653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -5.46	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 4.4	phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 660 bp · p 4.2e-12 · regional, not allelic
Overall
CADD	17.09	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 0.00267% African / African-American · 2/74,942 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,214 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: PTGS2
Protein: p.Lys355Glu
Coding: c.1063A>G
MANE Select: NM_000963
Type: single nucleotide variant
Location: chr1:186676092 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.37 · 7 PDB

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-lys355glu (accessed [today's date]).

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