Is UMPS p.Pro346= (c.1038A>G) pathogenic?

UMPS p.Pro346= (c.1038A>G) is classified Benign in UMPS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). Common (popmax 5.09%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Hereditary orotic aciduria, type 1.

What condition is associated with UMPS p.Pro346= (c.1038A>G)?

UMPS p.Pro346= (c.1038A>G) is associated with Hereditary orotic aciduria, type 1 (ClinVar).

UMPS p.Pro346=

Q: How common is UMPS p.Pro346= (c.1038A>G) in the general population?

UMPS p.Pro346= (c.1038A>G) is common (popmax 5.09%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1038A>G · rs17843835 · VCV342932

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 5.09%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Hereditary orotic aciduria, type 1

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 -2.7	GERP -5.5
Overall
CADD	2.838	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.09% African / African-American · 3,818/75,026 alleles

Filtering AF 4.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.9%

Overall 0.278% 4,493/1,614,136 alleles · common exomes 2,218/1,461,878 · genomes 2,275/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.09%	20
Admixed American	0.483%	207
Remaining individualsnot grpmax-eligible	0.466%	215
Middle Eastern	0.231%	432
South Asian	0.0132%	7,589
European (non-Finnish)	0.00576%	17,353

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.Pro346=
Coding: c.1038A>G
MANE Select: NM_000373
dbSNP: rs17843835
Type: single nucleotide variant
Location: chr3:124740079 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 125 PDB
Residue 346: the 'ompdecase' region

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-pro346 (accessed [today's date]).

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