Is P2RX2 p.Arg46Ser (c.136C>A) pathogenic?

P2RX2 p.Arg46Ser (c.136C>A) is classified Uncertain significance in P2RX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-14). AlphaMissense: likely pathogenic (0.9858); Very rare (popmax 0.00265%, sas).

How common is P2RX2 p.Arg46Ser (c.136C>A) in the general population?

P2RX2 p.Arg46Ser (c.136C>A) is very rare (popmax 0.00265%, sas) (gnomAD).

What do computational predictors say about P2RX2 p.Arg46Ser (c.136C>A)?

AlphaMissense predicts likely pathogenic (score 0.9858) — an in-silico prediction, not a clinical call.

P2RX2 p.Arg46Ser

c.136C>A · rs774203714 · VCV1966793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00265%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9858	likely pathogenic · top 6% in P2RX2
REVEL	0.289	benign-leaning
SaProt	LLR -13.65	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.4	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,152 bp · p 0.32 · regional, not allelic
Overall
CADD	25.3	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 0.00265% South Asian · 1/37,696 alleles

Filtering AF 9.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.2e-05%

Overall 0.000385% 5/1,298,876 alleles · very rare exomes 5/1,150,884 · genomes 0/147,992 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00265%	37,696
European (non-Finnish)	0.000395%	253,159

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: P2RX2
Protein: p.Arg46Ser
Coding: c.136C>A
MANE Select: NM_170682
dbSNP: rs774203714
Type: single nucleotide variant
Location: chr12:132618952 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 18 PDB

Full P2RX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

P2RX2 p.Arg46= Likely benign ★ same residue
P2RX2 c.174-1G>A Uncertain significance ★★ same type
P2RX2 p.Arg218His Uncertain significance ★★ ⚠ same type
P2RX2 p.Arg286Gln Uncertain significance ★★ ⚠ same type
P2RX2 p.Arg302Thr Uncertain significance ★★ ⚠ same type
P2RX2 p.Arg315Cys Uncertain significance ★★ ⚠ same type
P2RX2 p.Arg315His Uncertain significance ★★ ⚠ same type
P2RX2 p.Arg324Cys 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/p2rx2-p-arg46ser (accessed [today's date]).

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