Is IDS p.Arg493Cys (c.1477C>T) pathogenic?

IDS p.Arg493Cys (c.1477C>T) is classified Conflicting classifications of pathogenicity in IDS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: ambiguous (0.4635); Very rare (popmax 0.00218%, amr); Associated with mucopolysaccharidosis type 2.

What condition is associated with IDS p.Arg493Cys (c.1477C>T)?

IDS p.Arg493Cys (c.1477C>T) is associated with mucopolysaccharidosis type 2 (ClinVar).

How common is IDS p.Arg493Cys (c.1477C>T) in the general population?

IDS p.Arg493Cys (c.1477C>T) is very rare (popmax 0.00218%, amr) (gnomAD).

How is Mucopolysaccharidosis type 2 inherited?

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

What do computational predictors say about IDS p.Arg493Cys (c.1477C>T)?

AlphaMissense predicts ambiguous (score 0.4635) — an in-silico prediction, not a clinical call.

IDS p.Arg493Cys

c.1477C>T · rs782190885 · VCV1404345

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mucopolysaccharidosis type 2

Computational evidence

Protein change
AlphaMissense	0.4635	ambiguous
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 21 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	27.2	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 0.00218% Admixed American · 1/45,788 alleles

Filtering AF 0.000325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000744% 9/1,209,710 alleles · very rare exomes 8/1,097,705 · genomes 1/112,005 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,032
Admixed Americangrpmax	0.00218%	45,788
European (non-Finnish)	0.000782%	127,838

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: IDS
Protein: p.Arg493Cys
Coding: c.1477C>T
MANE Select: NM_000202
dbSNP: rs782190885
Type: single nucleotide variant
Location: chrX:149482922 (GRCh38)
Structure: AlphaFold pLDDT 93.39 · 2 PDB
Residue 493: a β-strand

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

Disease context

mucopolysaccharidosis type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucopolysaccharidosis type 2 (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

IDS p.Arg493Pro Pathogenic/Likely pathogenic ★★ same residue
IDS p.Arg493His Conflicting classifications of pathogenicity ★ ⚠ same residue
IDS p.Arg493= Likely benign ★ same residue
IDS c.1006+1G>C Pathogenic ★★ same condition
IDS c.1006+1G>T Pathogenic ★★ same condition
IDS c.1007-133A>G Likely pathogenic ★★ same condition
IDS c.1007-1G>A Pathogenic ★★ same condition
IDS c.1007-2A>C Pathogenic/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/ids-p-arg493cys (accessed [today's date]).

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