Is UMPS p.Met247Arg (c.740T>G) pathogenic?

UMPS p.Met247Arg (c.740T>G) is classified Uncertain significance in UMPS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-28). AlphaMissense: likely pathogenic (0.8378); Absent from gnomAD v4.1; Associated with Hereditary orotic aciduria, type 1.

What condition is associated with UMPS p.Met247Arg (c.740T>G)?

UMPS p.Met247Arg (c.740T>G) is associated with Hereditary orotic aciduria, type 1 (ClinVar).

How common is UMPS p.Met247Arg (c.740T>G) in the general population?

UMPS p.Met247Arg (c.740T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about UMPS p.Met247Arg (c.740T>G)?

AlphaMissense predicts likely pathogenic (score 0.8378) — an in-silico prediction, not a clinical call.

UMPS p.Met247Arg

c.740T>G · rs2063529521 · VCV1417735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8378 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary orotic aciduria, type 1

Computational evidence

Protein change
AlphaMissense	0.8378	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -15.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 14 kb · p 0.016 · regional, not allelic
Overall
CADD	26.8	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

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: UMPS
Protein: p.Met247Arg
Coding: c.740T>G
MANE Select: NM_000373
dbSNP: rs2063529521
Type: single nucleotide variant
Location: chr3:124737997 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 125 PDB
Residue 247: the 'ompdecase' region; an α-helix

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

Disease context

Hereditary orotic aciduria, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UMPS p.Ala4Pro Uncertain significance ★★ ⚠ same condition
UMPS p.Arg313Trp Uncertain significance ★★ ⚠ same condition
UMPS p.Gly167Arg Uncertain significance ★★ ⚠ same condition
UMPS p.Ser276Asn Uncertain significance ★★ ⚠ same condition
UMPS p.Ser404Phe Uncertain significance ★★ ⚠ same condition
UMPS c.1159-19C>T Likely benign ★★ same condition
UMPS c.*28A>G Benign ★★ same condition
UMPS p.Gly213Ala Benign ★★ same condition

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/umps-p-met247arg (accessed [today's date]).

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