Is UMOD p.Leu599Pro (c.1796T>C) pathogenic?

UMOD p.Leu599Pro (c.1796T>C) is classified Uncertain significance in UMOD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: likely pathogenic (0.9577); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with UMOD p.Leu599Pro (c.1796T>C)?

UMOD p.Leu599Pro (c.1796T>C) is associated with Inborn genetic diseases (ClinVar).

How common is UMOD p.Leu599Pro (c.1796T>C) in the general population?

UMOD p.Leu599Pro (c.1796T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about UMOD p.Leu599Pro (c.1796T>C)?

AlphaMissense predicts likely pathogenic (score 0.9577) — an in-silico prediction, not a clinical call.

UMOD p.Leu599Pro

c.1796T>C · rs2507336153 · VCV2544437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9577 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9577	likely pathogenic · top 3% in UMOD
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -14.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 17 kb · p 0.0029 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Overall 6.2e-05% 1/1,614,094 alleles · very rare exomes 1/1,461,790 · genomes 0/152,304 · joint denominator

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: UMOD
Protein: p.Leu599Pro
Coding: c.1796T>C
MANE Select: NM_003361
dbSNP: rs2507336153
Type: single nucleotide variant
Location: chr16:20336672 (GRCh38)
Gene constraint: LOEUF 1.241 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.00 · 10 PDB
Residue 599: a β-strand; the 'external hydrophobic patch (ehp); regulates polymerization into filaments' region

Full UMOD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UMOD p.Ala39Asp Uncertain significance ★★ ⚠ same condition
UMOD p.Arg365Trp Uncertain significance ★★ ⚠ same condition
UMOD p.Arg415His Uncertain significance ★★ same condition
UMOD p.Arg547Gln Uncertain significance ★★ ⚠ same condition
UMOD p.Asp355Asn Uncertain significance ★★ ⚠ same condition
UMOD p.Gly158Arg Uncertain significance ★★ ⚠ same condition
UMOD p.Gly546Ser Uncertain significance ★★ ⚠ same condition
UMOD p.Gly590Arg Uncertain significance ★★ ⚠ 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/umod-p-leu599pro (accessed [today's date]).

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