Is UMPS p.Ile446Val (c.1336A>G) pathogenic?

UMPS p.Ile446Val (c.1336A>G) is classified Benign in UMPS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0707); Common (popmax 6.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Oroticaciduria.

What condition is associated with UMPS p.Ile446Val (c.1336A>G)?

UMPS p.Ile446Val (c.1336A>G) is associated with Oroticaciduria (ClinVar).

What do computational predictors say about UMPS p.Ile446Val (c.1336A>G)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

UMPS p.Ile446Val

Q: How common is UMPS p.Ile446Val (c.1336A>G) in the general population?

UMPS p.Ile446Val (c.1336A>G) is common (popmax 6.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1336A>G · rs3772809 · VCV342935

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Oroticaciduria

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.74	GERP -0.64, phastCons 0.011
Regional constraint	o/e 0.90	unconstrained · MANE · 14 kb · p 0.016 · regional, not allelic
Overall
CADD	13.06	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 6.1% East Asian · 2,736/44,876 alleles

Filtering AF 5.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.83%

Overall 1.55% 25,003/1,614,206 alleles · common exomes 22,978/1,461,852 · genomes 2,025/152,354 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	6.1%	16
South Asian	4.11%	24
Admixed American	3.83%	26
Remaining individualsnot grpmax-eligible	1.59%	63
European (non-Finnish)	1.22%	82
Ashkenazi Jewishnot grpmax-eligible	0.841%	119
Finnishnot grpmax-eligible	0.7%	143
Middle Eastern	0.495%	202
African / African-American	0.221%	452

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.Ile446Val
Coding: c.1336A>G
MANE Select: NM_000373
dbSNP: rs3772809
Type: single nucleotide variant
Location: chr3:124743977 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 125 PDB
Residue 446: a UniProt-annotated variant site (in); 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-ile446val (accessed [today's date]).

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