Is PTGS2 p.Ala436Ser (c.1306G>T) pathogenic?

PTGS2 p.Ala436Ser (c.1306G>T) is classified Uncertain significance in PTGS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: likely benign (0.1095); Very rare (popmax 0.00805%, nfe).

How common is PTGS2 p.Ala436Ser (c.1306G>T) in the general population?

PTGS2 p.Ala436Ser (c.1306G>T) is very rare (popmax 0.00805%, nfe) (gnomAD).

What do computational predictors say about PTGS2 p.Ala436Ser (c.1306G>T)?

AlphaMissense predicts likely benign (score 0.1095) — an in-silico prediction, not a clinical call.

PTGS2 p.Ala436Ser

c.1306G>T · rs139215497 · VCV2218758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00805%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1095	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -6.92	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 5.9	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,648 bp · p 0.0031 · regional, not allelic
Overall
CADD	20.7	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 0.00805% European (non-Finnish) · 95/1,180,040 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00624%

Overall 0.00626% 101/1,614,046 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00805%	12,421
Admixed American	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ala436Ser
Coding: c.1306G>T
MANE Select: NM_000963
dbSNP: rs139215497
Type: single nucleotide variant
Location: chr1:186675348 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.37 · 7 PDB
Residue 436: 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.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
PTGS2 p.Ala581Thr 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-ala436ser (accessed [today's date]).

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