Is UMPS p.Arg313Trp (c.937C>T) pathogenic?

UMPS p.Arg313Trp (c.937C>T) is classified Uncertain significance in UMPS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-29). AlphaMissense: ambiguous (0.5639); Ultra-rare (popmax 0.0164%, mid); Associated with Hereditary orotic aciduria, type 1.

What condition is associated with UMPS p.Arg313Trp (c.937C>T)?

UMPS p.Arg313Trp (c.937C>T) is associated with Hereditary orotic aciduria, type 1 (ClinVar).

How common is UMPS p.Arg313Trp (c.937C>T) in the general population?

UMPS p.Arg313Trp (c.937C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about UMPS p.Arg313Trp (c.937C>T)?

AlphaMissense predicts ambiguous (score 0.5639) — an in-silico prediction, not a clinical call.

UMPS p.Arg313Trp

c.937C>T · rs375821728 · VCV1809913

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5639 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Hereditary orotic aciduria, type 1

Computational evidence

Protein change
AlphaMissense	0.5639	ambiguous
REVEL	0.7	pathogenic-leaning
SaProt	LLR -16.97	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 14 kb · p 0.016 · regional, not allelic
Overall
CADD	31.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00229% 37/1,613,860 alleles · ultra-rare exomes 27/1,461,774 · genomes 10/152,086 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00445%	22,450
European (non-Finnish)	0.0022%	45,386
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,038

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg313Trp
Coding: c.937C>T
MANE Select: NM_000373
dbSNP: rs375821728
Type: single nucleotide variant
Location: chr3:124738194 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 125 PDB
Residue 313: the 'ompdecase' region; a β-strand

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.Arg313Gln Uncertain significance ★ ⚠ same residue
UMPS p.Ala4Pro 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-arg313trp (accessed [today's date]).

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