Is UMPS p.Asp458= (c.1374T>C) pathogenic?

UMPS p.Asp458= (c.1374T>C) is classified Benign/Likely benign in UMPS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-09). Rare (popmax 0.45%, eas); Associated with Oroticaciduria.

What condition is associated with UMPS p.Asp458= (c.1374T>C)?

UMPS p.Asp458= (c.1374T>C) is associated with Oroticaciduria (ClinVar).

How common is UMPS p.Asp458= (c.1374T>C) in the general population?

UMPS p.Asp458= (c.1374T>C) is rare (popmax 0.45%, eas) (gnomAD).

UMPS p.Asp458=

c.1374T>C · rs200608473 · VCV342936

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.45%, eas)

Conditions

Oroticaciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.46	GERP -2.2, phastCons 0.64
Overall
CADD	2.807	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.45% East Asian · 202/44,888 alleles

Filtering AF 0.399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.38%

Overall 0.013% 210/1,614,240 alleles · rare exomes 184/1,461,876 · genomes 26/152,364 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.45%	222
Remaining individualsnot grpmax-eligible	0.0112%	8,930
European (non-Finnish)	8.47e-05%	1,180,040

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: UMPS
Protein: p.Asp458=
Coding: c.1374T>C
MANE Select: NM_000373
dbSNP: rs200608473
Type: single nucleotide variant
Location: chr3:124744015 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 125 PDB
Residue 458: the 'ompdecase' region; a β-strand

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

Disease context

Oroticaciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UMPS c.*37C>T Uncertain significance ★★ same condition
UMPS p.Ala386= Uncertain significance ★★ same condition
UMPS p.Arg363Gln Uncertain significance ★★ ⚠ same condition
UMPS p.Asp271His Uncertain significance ★★ ⚠ same condition
UMPS c.*1051G>T Benign ★★ same condition
UMPS c.*1211C>A Benign ★★ same condition
UMPS c.*4430C>T Benign ★★ same condition
UMPS c.*725A>T 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-asp458 (accessed [today's date]).

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