Is MTREX p.His300Arg (c.899A>G) pathogenic?

MTREX p.His300Arg (c.899A>G) is classified Uncertain significance in MTREX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). AlphaMissense: likely pathogenic (0.9263); Very rare (popmax 0.00337%, amr).

How common is MTREX p.His300Arg (c.899A>G) in the general population?

MTREX p.His300Arg (c.899A>G) is very rare (popmax 0.00337%, amr) (gnomAD).

What do computational predictors say about MTREX p.His300Arg (c.899A>G)?

AlphaMissense predicts likely pathogenic (score 0.9263) — an in-silico prediction, not a clinical call.

MTREX p.His300Arg

c.899A>G · rs1173404117 · VCV2568481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00337%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9263	likely pathogenic
REVEL	0.49	indeterminate
SaProt	LLR -11.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 5,076 bp · p 8.7e-16 · regional, not allelic
Overall
CADD	24.3	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 0.00337% Admixed American · 2/59,360 alleles

Filtering AF 0.000559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000869% 14/1,611,342 alleles · very rare exomes 13/1,459,154 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00337%	29,680
African / African-American	0.00268%	37,368
Remaining individualsnot grpmax-eligible	0.0016%	62,366
European (non-Finnish)	0.000763%	131,023

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.His300Arg
Coding: c.899A>G
MANE Select: NM_015360
dbSNP: rs1173404117
Type: single nucleotide variant
Location: chr5:55343448 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.68 · 11 PDB
Residue 300: the helicase atp-binding domain; an α-helix

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-his300arg (accessed [today's date]).

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