Is MRGPRX1 p.Leu22Pro (c.65T>C) pathogenic?

MRGPRX1 p.Leu22Pro (c.65T>C) is classified Likely benign in MRGPRX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely benign (0.0593); Ultra-rare (popmax 0.0498%, mid).

How common is MRGPRX1 p.Leu22Pro (c.65T>C) in the general population?

MRGPRX1 p.Leu22Pro (c.65T>C) is ultra-rare (popmax 0.0498%, mid) (gnomAD).

What do computational predictors say about MRGPRX1 p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

MRGPRX1 p.Leu22Pro

c.65T>C · VCV4552945

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0498%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.7
Regional constraint	o/e 1.04	unconstrained · MANE · 965 bp · p 0.39 · regional, not allelic
Overall
CADD	0.03	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 0.0498% Middle Eastern · 3/6,030 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00124% 18/1,456,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0498%	2,010
East Asian	0.00223%	44,774
Remaining individualsnot grpmax-eligible	0.00161%	62,300
European (non-Finnish)	0.0011%	90,545

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: MRGPRX1
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_001393578
Type: single nucleotide variant
Location: chr11:18934720 (GRCh38)
Gene constraint: LOEUF 1.818 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 82.85 · 7 PDB
Residue 22: a functional site (cleavage; by d.pteronyssinus der p 1)

Full MRGPRX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MRGPRX1 p.Arg55Leu Benign ★★ ⚠ same type
MRGPRX1 p.Leu223= Benign ★★ same type
MRGPRX1 p.Ala115Gly Uncertain significance ★ ⚠ same type
MRGPRX1 p.Ala182Ser Uncertain significance ★ ⚠ same type
MRGPRX1 p.Ala70Ser Uncertain significance ★ ⚠ same type
MRGPRX1 p.Arg120Cys Uncertain significance ★ ⚠ same type
MRGPRX1 p.Arg134Leu Uncertain significance ★ ⚠ same type
MRGPRX1 p.Arg293Trp 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/mrgprx1-p-leu22pro (accessed [today's date]).

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