# NM_000202.8(IDS):c.103G>C (p.Asp35His)

https://sugi.bio/variant/ids-p-asp35his

## Summary

**IDS p.Asp35His (c.103G>C)** is classified **Likely pathogenic** in IDS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-07). AlphaMissense: likely benign (0.0884); Absent from gnomAD v4.1; Associated with mucopolysaccharidosis type 2.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs2089514224 · 3 submitters · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the IDS gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to mucopolysaccharidosis type 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 42 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | IDS is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Mucopolysaccharidosis type 2** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Macrocephaly — Very frequent (99-80%)
- Coarse facial features — Very frequent (99-80%)
- Limitation of joint mobility — Very frequent (99-80%)
- Abnormal heart morphology — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Inguinal hernia — Frequent (79-30%)
- Macroglossia — Frequent (79-30%)
- Gingival overgrowth — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006675/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [IDS](https://sugi.bio/atlas/gene/IDS/) |
| Protein change (HGVS p.) | p.Asp35His |
| Coding change (HGVS c.) | c.103G>C |
| MANE Select transcript | [NM_000202](https://www.ncbi.nlm.nih.gov/nuccore/NM_000202) |
| dbSNP | [rs2089514224](https://www.ncbi.nlm.nih.gov/snp/rs2089514224/) |
| Variant type | single nucleotide variant |
| Location | chrX:149505035-149505035 (GRCh38) |
| ClinVar | [VCV988665](https://www.ncbi.nlm.nih.gov/clinvar/variation/988665/) |

**All HGVS expressions:** `NC_000023.10:g.148586565C>G`, `NC_000023.11:g.149505035C>G`, `NG_011900.3:g.5300G>C`, `NM_000202.8:c.103G>C`, `NM_001166550.4:c.-124G>C`, `NM_006123.5:c.103G>C`, `NR_104128.2:n.272G>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.0884) — ⚠ discordant with the pathogenic call
- REVEL 0.421 (indeterminate)
- SaProt LLR -3.771 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.85) — consistent with the pathogenic call
- Conservation: phyloP 6.567, GERP 1.28, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.34** across the covering region of the MANE Select transcript (149,504,279–149,505,137), spanning 858 bp. Chi-square p 0.049. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.85**, acceptor gain **0.00**, donor gain **0.06**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.85**, acceptor gain **0.00**, donor gain **0.07**.
- Pangolin: Δ**0.78** (loss), gain 0.02 / loss 0.78. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**IDS** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mucopolysaccharidosis type 2** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.39, 88% of residues very-high.

**2 experimental structure(s)** (PDB): [5FQL](https://www.rcsb.org/structure/5FQL), [6IOZ](https://www.rcsb.org/structure/6IOZ).

## What this gene does {#gene-function}

*Describes the biological roles of IDS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** IDS's established molecular role includes iduronate-2-sulfatase activity. In Reactome, IDS is annotated in disease pathway(s) including **MPS II - Hunter syndrome (CS/DS degradation)**, **MPS II - Hunter syndrome (HS-GAG degradation)**.

**Disease mechanism (Reactome):** IDS loss or alteration is curated in [MPS II - Hunter syndrome (CS/DS degradation)](https://reactome.org/content/detail/R-HSA-9953078), [MPS II - Hunter syndrome (HS-GAG degradation)](https://reactome.org/content/detail/R-HSA-2206296).

### Pathways affected {#pathways}

IDS participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [MPS II - Hunter syndrome (CS/DS degradation)](https://reactome.org/content/detail/R-HSA-9953078) | curated |
| ⚕ [MPS II - Hunter syndrome (HS-GAG degradation)](https://reactome.org/content/detail/R-HSA-2206296) | curated |
| [CS/DS degradation](https://reactome.org/content/detail/R-HSA-2024101) | curated |
| [HS-GAG degradation](https://reactome.org/content/detail/R-HSA-2024096) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** iduronate-2-sulfatase activity, calcium ion binding.

**Biological process:** glycosaminoglycan catabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-07.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics | Pathogenic | no assertion criteria provided | research |  |
| Mayo Clinic Laboratories, Mayo Clinic | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-06 |
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Likely pathogenic | criteria provided, single submitter | literature only | 2024-06-07 |

## Associated conditions {#conditions}

[mucopolysaccharidosis type 2](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-2/).

**Reported phenotype names (ClinVar):** Mucopolysaccharidosis, MPS-II, not provided, none provided, IDS deficiency, Sulfoiduronate sulfatase deficiency, SIDS deficiency, Mucopolysaccharidosis type 2, Mucopolysaccharidosis Type II, Attenuated MPS (subtype; formerly known as mild MPS II), Severe MPS II.

## Same-residue context {#hotspot}

Residue **35** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [IDS p.Asp35fs](/variant/ids-p-asp35fs), [IDS p.Asp35Tyr](/variant/ids-p-asp35tyr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related IDS variant pages (same residue, condition, or type): [IDS p.Asp35Gly](/variant/ids-p-asp35gly), [IDS p.Asp35fs](/variant/ids-p-asp35fs), [IDS p.Asp35Tyr](/variant/ids-p-asp35tyr), [IDS p.Asp35Val](/variant/ids-p-asp35val), [IDS c.1006+1G>C](/variant/ids-c-1006-plus-1g-c), [IDS c.1006+1G>T](/variant/ids-c-1006-plus-1g-t), [IDS c.1007-133A>G](/variant/ids-c-1007-minus-133a-g), [IDS c.1007-1G>A](/variant/ids-c-1007-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 988665). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*