Is UMPS p.Phe227= (c.681C>T) pathogenic?

UMPS p.Phe227= (c.681C>T) is classified Likely benign in UMPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). Ultra-rare (popmax 0.022%, sas); Associated with Hereditary orotic aciduria, type 1.

What condition is associated with UMPS p.Phe227= (c.681C>T)?

UMPS p.Phe227= (c.681C>T) is associated with Hereditary orotic aciduria, type 1 (ClinVar).

How common is UMPS p.Phe227= (c.681C>T) in the general population?

UMPS p.Phe227= (c.681C>T) is ultra-rare (popmax 0.022%, sas) (gnomAD).

UMPS p.Phe227=

c.681C>T · rs148036615 · VCV712330

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

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 -0.13	GERP -3.1, phastCons 0.75
Overall
CADD	6.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.022% South Asian · 20/91,082 alleles

Filtering AF 0.016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0152%

Overall 0.0159% 256/1,614,198 alleles · ultra-rare exomes 240/1,461,888 · genomes 16/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,554
Remaining individualsnot grpmax-eligible	0.0208%	4,808
European (non-Finnish)	0.0181%	5,540
African / African-American	0.008%	12,507
Admixed American	0.005%	20,008
East Asian	0.00223%	44,886

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.Phe227=
Coding: c.681C>T
MANE Select: NM_000373
dbSNP: rs148036615
Type: single nucleotide variant
Location: chr3:124737938 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 125 PDB
Residue 227: 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-phe227 (accessed [today's date]).

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