Is MTREX p.His278Arg (c.833A>G) pathogenic?

MTREX p.His278Arg (c.833A>G) is classified Uncertain significance in MTREX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely benign (0.1742); Very rare (popmax 6.2e-05%).

How common is MTREX p.His278Arg (c.833A>G) in the general population?

MTREX p.His278Arg (c.833A>G) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about MTREX p.His278Arg (c.833A>G)?

AlphaMissense predicts likely benign (score 0.1742) — an in-silico prediction, not a clinical call.

MTREX p.His278Arg

c.833A>G · VCV3399650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1742	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.26 · evaluated, not missing
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	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 6.2e-05%

Overall 6.2e-05% 1/1,613,154 alleles · very rare exomes 1/1,460,892 · genomes 0/152,262 · 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: MTREX
Protein: p.His278Arg
Coding: c.833A>G
MANE Select: NM_015360
Type: single nucleotide variant
Location: chr5:55343382 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.68 · 11 PDB
Residue 278: the helicase atp-binding domain; a β-strand

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

Similar variants

PLPP1 p.Tyr278His Uncertain significance ★ ⚠ same residue
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

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-his278arg (accessed [today's date]).

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