Is MTREX p.Pro137Leu (c.410C>T) pathogenic?

MTREX p.Pro137Leu (c.410C>T) is classified Uncertain significance in MTREX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: ambiguous (0.4748); Ultra-rare (popmax 0.0167%, amr).

How common is MTREX p.Pro137Leu (c.410C>T) in the general population?

MTREX p.Pro137Leu (c.410C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about MTREX p.Pro137Leu (c.410C>T)?

AlphaMissense predicts ambiguous (score 0.4748) — an in-silico prediction, not a clinical call.

MTREX p.Pro137Leu

c.410C>T · VCV3914431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4748	ambiguous
REVEL	0.409	indeterminate
SaProt	LLR -14.79	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 16 kb · p 0.014 · regional, not allelic
Overall
CADD	27.0	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 0.0167% Admixed American · 10/59,858 alleles

Filtering AF 0.00902% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00683%

Overall 0.00174% 28/1,606,362 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,986
East Asian	0.00223%	44,774
African / African-American	0.00134%	74,616
European (non-Finnish)	0.00128%	78,250
South Asian	0.0011%	90,818

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.Pro137Leu
Coding: c.410C>T
MANE Select: NM_015360
Type: single nucleotide variant
Location: chr5:55328706 (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-pro137leu (accessed [today's date]).

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