Is MRTO4 p.Pro2Arg (c.5C>G) pathogenic?

MRTO4 p.Pro2Arg (c.5C>G) is classified Uncertain significance in MRTO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.9803); Very rare (popmax 0.000771%, nfe).

How common is MRTO4 p.Pro2Arg (c.5C>G) in the general population?

MRTO4 p.Pro2Arg (c.5C>G) is very rare (popmax 0.000771%, nfe) (gnomAD).

What do computational predictors say about MRTO4 p.Pro2Arg (c.5C>G)?

AlphaMissense predicts likely pathogenic (score 0.9803) — an in-silico prediction, not a clinical call.

MRTO4 p.Pro2Arg

c.5C>G · VCV4110881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000771%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9803	likely pathogenic
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -14.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,991 bp · p 0.83 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000771% European (non-Finnish) · 9/1,167,660 alleles

Filtering AF 0.000363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000263%

Overall 0.000567% 9/1,587,106 alleles · very rare exomes 6/1,434,876 · genomes 3/152,230 · joint denominator

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: MRTO4
Protein: p.Pro2Arg
Coding: c.5C>G
MANE Select: NM_016183
Type: single nucleotide variant
Location: chr1:19251840 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 89.84 · 35 PDB

Full MRTO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MRTO4 c.493+2T>A Uncertain significance ★ same type
MRTO4 p.Ala59Thr Uncertain significance ★ ⚠ same type
MRTO4 p.Arg107Ser Uncertain significance ★ ⚠ same type
MRTO4 p.Arg126Leu Uncertain significance ★ ⚠ same type
MRTO4 p.Arg126Pro Uncertain significance ★ ⚠ same type
MRTO4 p.Arg188His Uncertain significance ★ ⚠ same type
MRTO4 p.Arg214Ser Uncertain significance ★ ⚠ same type
MRTO4 p.Arg57Gln 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/mrto4-p-pro2arg (accessed [today's date]).

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