Is MTREX p.His594Arg (c.1781A>G) pathogenic?

MTREX p.His594Arg (c.1781A>G) is classified Uncertain significance in MTREX (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.5503); Absent from gnomAD v4.1; Associated with Marfanoid habitus and intellectual disability.

What condition is associated with MTREX p.His594Arg (c.1781A>G)?

MTREX p.His594Arg (c.1781A>G) is associated with Marfanoid habitus and intellectual disability (ClinVar).

How common is MTREX p.His594Arg (c.1781A>G) in the general population?

MTREX p.His594Arg (c.1781A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTREX p.His594Arg (c.1781A>G)?

AlphaMissense predicts ambiguous (score 0.5503) — an in-silico prediction, not a clinical call.

MTREX p.His594Arg

c.1781A>G · rs1579873373 · VCV689688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5503 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Marfanoid habitus and intellectual disability

Computational evidence

Protein change
AlphaMissense	0.5503	ambiguous
REVEL	0.265	benign-leaning
SaProt	LLR -9.67	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 66 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	23.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTREX
Protein: p.His594Arg
Coding: c.1781A>G
MANE Select: NM_015360
dbSNP: rs1579873373
Type: single nucleotide variant
Location: chr5:55366846 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.68 · 11 PDB
Residue 594: an α-helix

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

Disease context

Marfanoid habitus and intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-his594arg (accessed [today's date]).

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