Is IDS p.His342Arg (c.1025A>G) pathogenic?

IDS p.His342Arg (c.1025A>G) is classified Conflicting classifications of pathogenicity in IDS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-31). AlphaMissense: ambiguous (0.4576); Very rare (popmax 0.000112%, nfe); Associated with mucopolysaccharidosis type 2.

What condition is associated with IDS p.His342Arg (c.1025A>G)?

IDS p.His342Arg (c.1025A>G) is associated with mucopolysaccharidosis type 2 (ClinVar).

How common is IDS p.His342Arg (c.1025A>G) in the general population?

IDS p.His342Arg (c.1025A>G) is very rare (popmax 0.000112%, nfe) (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.His342Arg (c.1025A>G)?

AlphaMissense predicts ambiguous (score 0.4576) — an in-silico prediction, not a clinical call.

IDS p.His342Arg

c.1025A>G · VCV3255925

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

mucopolysaccharidosis type 2

Computational evidence

Protein change
AlphaMissense	0.4576	ambiguous
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -8.53	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 21 kb · p 5.6e-05 · 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 0.000112% European (non-Finnish) · 1/895,339 alleles

Overall 8.25e-05% 1/1,211,553 alleles · very rare exomes 1/1,097,981 · genomes 0/113,572 · 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: IDS
Protein: p.His342Arg
Coding: c.1025A>G
MANE Select: NM_000202
Type: single nucleotide variant
Location: chrX:149487080 (GRCh38)
Structure: AlphaFold pLDDT 93.39 · 2 PDB
Residue 342: a UniProt-annotated variant site (in mps2; mild form); an α-helix

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.His342Pro Likely pathogenic ★★ same residue
IDS p.His342Tyr Likely pathogenic ★★ same residue
IDS p.His342Leu Likely pathogenic ★ same residue
IDS p.His342_Gly343delinsGlnTer Pathogenic ★ same residue
IDS p.His342fs Pathogenic ★ 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

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-his342arg (accessed [today's date]).

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