Is P2RX2 p.Phe378Ser (c.1133T>C) pathogenic?

P2RX2 p.Phe378Ser (c.1133T>C) is classified Conflicting classifications of pathogenicity in P2RX2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-12). AlphaMissense: likely pathogenic (0.9664); Ultra-rare (popmax 0.0329%, mid); Associated with Bilateral sensorineural hearing impairment.

What condition is associated with P2RX2 p.Phe378Ser (c.1133T>C)?

P2RX2 p.Phe378Ser (c.1133T>C) is associated with Bilateral sensorineural hearing impairment (ClinVar).

How common is P2RX2 p.Phe378Ser (c.1133T>C) in the general population?

P2RX2 p.Phe378Ser (c.1133T>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about P2RX2 p.Phe378Ser (c.1133T>C)?

AlphaMissense predicts likely pathogenic (score 0.9664) — an in-silico prediction, not a clinical call.

P2RX2 p.Phe378Ser

c.1133T>C · rs143626910 · VCV1185581

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9664 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Bilateral sensorineural hearing impairment

Computational evidence

Protein change
AlphaMissense	0.9664	likely pathogenic
REVEL	0.354	indeterminate
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,152 bp · p 0.32 · regional, not allelic
Overall
CADD	27.9	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00266% 43/1,613,610 alleles · ultra-rare exomes 30/1,461,506 · genomes 13/152,104 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
African / African-American	0.028%	3,567
South Asian	0.00659%	15,163
Admixed American	0.00334%	29,966
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	0.000932%	107,263

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.Phe378Ser
Coding: c.1133T>C
MANE Select: NM_170682
dbSNP: rs143626910
Type: single nucleotide variant
Location: chr12:132621689 (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

Disease context

Bilateral sensorineural hearing impairment — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
P2RX2 p.Asp180Asn 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-phe378ser (accessed [today's date]).

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