Is IDUA p.Pro533Ser (c.1597C>T) pathogenic?

IDUA p.Pro533Ser (c.1597C>T) is classified Conflicting classifications of pathogenicity in IDUA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-15). AlphaMissense: likely pathogenic (0.8225); Ultra-rare (popmax 0.0149%, eas); Associated with mucopolysaccharidosis type 1.

What condition is associated with IDUA p.Pro533Ser (c.1597C>T)?

IDUA p.Pro533Ser (c.1597C>T) is associated with mucopolysaccharidosis type 1 (ClinVar).

How common is IDUA p.Pro533Ser (c.1597C>T) in the general population?

IDUA p.Pro533Ser (c.1597C>T) is ultra-rare (popmax 0.0149%, eas) (gnomAD).

How is Mucopolysaccharidosis type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about IDUA p.Pro533Ser (c.1597C>T)?

AlphaMissense predicts likely pathogenic (score 0.8225) — an in-silico prediction, not a clinical call.

IDUA p.Pro533Ser

c.1597C>T · rs374779600 · VCV2201882

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8225 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0149%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mucopolysaccharidosis type 1

Computational evidence

Protein change
AlphaMissense	0.8225	likely pathogenic
REVEL	0.623	indeterminate
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 17 kb · p 0.00042 · regional, not allelic
Overall
CADD	24.6	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 0.0149% East Asian · 6/40,182 alleles

Filtering AF 0.00645% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00441%

Overall 0.000392% 6/1,528,720 alleles · ultra-rare

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: IDUA
Protein: p.Pro533Ser
Coding: c.1597C>T
MANE Select: NM_000203
dbSNP: rs374779600
Type: single nucleotide variant
Location: chr4:1003417 (GRCh38)
Gene constraint: LOEUF 1.344 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.12 · 11 PDB
Residue 533: a β-strand; a UniProt-annotated variant site (in mps1h and mps1h/s; in 3% of the mps1h patients; reduces catalytic activity and protein stability)

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

Disease context

mucopolysaccharidosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucopolysaccharidosis type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

IDUA p.Pro533Arg Pathogenic ★★★ same residue
IDUA p.Pro533Leu Pathogenic/Likely pathogenic ★★ same residue
IDUA p.Pro533Thr Likely pathogenic ★ ⚠ same residue
IDUA p.Pro533Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
IDUA p.Pro533= Likely benign ★ same residue
IDUA c.1190-10C>A Likely pathogenic ★★★ same condition
IDUA c.1190-1G>A Pathogenic ★★★ same condition
IDUA c.1402+1G>A Likely pathogenic ★★★ 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/idua-p-pro533ser (accessed [today's date]).

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