Is UMPS p.Ser404Phe (c.1211C>T) pathogenic?

UMPS p.Ser404Phe (c.1211C>T) is classified Uncertain significance in UMPS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1323); Ultra-rare (popmax 0.0834%, sas); Associated with Hereditary orotic aciduria, type 1.

What condition is associated with UMPS p.Ser404Phe (c.1211C>T)?

UMPS p.Ser404Phe (c.1211C>T) is associated with Hereditary orotic aciduria, type 1 (ClinVar).

How common is UMPS p.Ser404Phe (c.1211C>T) in the general population?

UMPS p.Ser404Phe (c.1211C>T) is ultra-rare (popmax 0.0834%, sas) (gnomAD).

What do computational predictors say about UMPS p.Ser404Phe (c.1211C>T)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

UMPS p.Ser404Phe

c.1211C>T · rs547350809 · VCV661312

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0834%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary orotic aciduria, type 1

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -11.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 14 kb · p 0.016 · regional, not allelic
Overall
CADD	25.9	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 0.0834% South Asian · 76/91,074 alleles

Filtering AF 0.0683% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0628%

Overall 0.0052% 84/1,614,056 alleles · ultra-rare exomes 76/1,461,870 · genomes 8/152,186 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0834%	1,198
Remaining individualsnot grpmax-eligible	0.008%	12,501
European (non-Finnish)	0.000254%	393,337

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.Ser404Phe
Coding: c.1211C>T
MANE Select: NM_000373
dbSNP: rs547350809
Type: single nucleotide variant
Location: chr3:124742204 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 125 PDB
Residue 404: 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 c.1159-19C>T Likely benign ★★ same condition
UMPS c.*28A>G Benign ★★ same condition
UMPS p.Gly213Ala Benign ★★ same condition
UMPS p.Gly440= 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-ser404phe (accessed [today's date]).

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