Is IDUA p.Pro221= (c.663C>T) pathogenic?

IDUA p.Pro221= (c.663C>T) is classified Likely benign in IDUA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-17). Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with IDUA p.Pro221= (c.663C>T)?

IDUA p.Pro221= (c.663C>T) is associated with Inborn genetic diseases, mucopolysaccharidosis type 1 (ClinVar).

How common is IDUA p.Pro221= (c.663C>T) in the general population?

IDUA p.Pro221= (c.663C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

IDUA p.Pro221=

c.663C>T · rs368553582 · VCV1108919

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -2.7
Overall
CADD	0.012	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,752 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000188% 3/1,597,570 alleles · very rare exomes 2/1,445,544 · genomes 1/152,026 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,752
European (non-Finnish)	0.00017%	588,654

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.Pro221=
Coding: c.663C>T
MANE Select: NM_000203
dbSNP: rs368553582
Type: single nucleotide variant
Location: chr4:1001752 (GRCh38)
Gene constraint: LOEUF 1.344 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.12 · 11 PDB
Residue 221: a β-strand

Full IDUA 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

Also linked: mucopolysaccharidosis type 1

Similar variants

SLC26A1 p.Val221Met Uncertain significance ★ ⚠ 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
IDUA c.1402+1G>T Likely pathogenic ★★★ same condition
IDUA c.1402+2T>G Likely pathogenic ★★★ same condition
IDUA c.1403-1G>T Pathogenic ★★★ same condition
IDUA c.1650+1G>T 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-pro221 (accessed [today's date]).

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