Is MTREX p.Arg751Gln (c.2252G>A) pathogenic?

MTREX p.Arg751Gln (c.2252G>A) is classified Uncertain significance in MTREX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely pathogenic (0.8037); Ultra-rare (popmax 0.0298%, sas).

How common is MTREX p.Arg751Gln (c.2252G>A) in the general population?

MTREX p.Arg751Gln (c.2252G>A) is ultra-rare (popmax 0.0298%, sas) (gnomAD).

What do computational predictors say about MTREX p.Arg751Gln (c.2252G>A)?

AlphaMissense predicts likely pathogenic (score 0.8037) — an in-silico prediction, not a clinical call.

MTREX p.Arg751Gln

c.2252G>A · rs757482394 · VCV3217573

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8037 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0298%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8037	likely pathogenic
REVEL	0.163	moderately benign-leaning
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 66 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	31.0	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 0.0298% South Asian · 27/90,484 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0181%

Overall 0.00292% 47/1,609,510 alleles · ultra-rare exomes 42/1,457,374 · genomes 5/152,136 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0298%	3,351
Finnishnot grpmax-eligible	0.0094%	10,640
Remaining individualsnot grpmax-eligible	0.00482%	20,743
East Asian	0.00446%	22,412
Admixed American	0.00167%	59,940
African / African-American	0.00134%	74,876
European (non-Finnish)	0.000595%	168,119

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: MTREX
Protein: p.Arg751Gln
Coding: c.2252G>A
MANE Select: NM_015360
dbSNP: rs757482394
Type: single nucleotide variant
Location: chr5:55397486 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.68 · 11 PDB

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

Similar variants

MTREX p.Ala247Pro Uncertain significance ★ ⚠ same type
MTREX p.Ala93Thr Uncertain significance ★ ⚠ same type
MTREX p.Ala974Thr Uncertain significance ★ ⚠ same type
MTREX p.Arg128Gln Uncertain significance ★ ⚠ same type
MTREX p.Arg184Cys Uncertain significance ★ ⚠ same type
MTREX p.Arg290Gln Uncertain significance ★ ⚠ same type
MTREX p.Arg364Gln Uncertain significance ★ ⚠ same type
MTREX p.Arg364Trp 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/mtrex-p-arg751gln (accessed [today's date]).

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