# NM_000202.8(IDS):c.782del (p.Pro261fs)

https://sugi.bio/variant/ids-p-pro261fs

## Summary

**IDS p.Pro261fs (c.782del)** is classified **Pathogenic** in IDS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-07). Very rare (popmax 0.000112%, nfe); Associated with mucopolysaccharidosis type 2.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2520851440 · 2 submitters · 1 linked condition · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the IDS gene that is considered disease-causing, submitted by 2 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.Pro261fs |
| Coding change (HGVS c.) | c.782del |
| MANE Select transcript | [NM_000202](https://www.ncbi.nlm.nih.gov/nuccore/NM_000202) |
| dbSNP | [rs2520851440](https://www.ncbi.nlm.nih.gov/snp/rs2520851440/) |
| Variant type | Deletion |
| Location | chrX:149496443-149496443 (GRCh38) |
| ClinVar | [VCV2737386](https://www.ncbi.nlm.nih.gov/clinvar/variation/2737386/) |

**All HGVS expressions:** `NC_000023.10:g.148577978del`, `NC_000023.11:g.149496447del`, `NG_011900.3:g.13892del`, `NG_042264.2:g.9803del`, `NM_000202.8:c.782del`, `NM_001166550.4:c.512del`, `NM_006123.5:c.782del`, `NR_104128.2:n.951del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.094, GERP -3.2, phastCons 0.012 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000112%** (nfe) · 1/892,962 in the highest group · 1/1,208,974 alleles overall — very rare (popmax 0.000112%, nfe).

*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}

Residue **261** lies in an α-helix.

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}

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

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Pathogenic | criteria provided, single submitter | literature only | 2024-06-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Mucopolysaccharidosis, MPS-II, Mucopolysaccharidosis with skin involvement, Mucopolysaccharidosis type 2, Attenuated MPS (subtype; formerly known as mild MPS II), Severe MPS II, I2S deficiency, MPS 2, Hunter Syndrome, IDURONATE 2-SULFATASE DEFICIENCY, Mucopolysaccharidosis Type II.

## Similar variants {#similar}

Related IDS variant pages (same residue, condition, or type): [IDS p.Pro261Ser](/variant/ids-p-pro261ser), [IDS p.Pro261Ala](/variant/ids-p-pro261ala), [IDS p.Pro261=](/variant/ids-p-pro261), [IDS p.Pro261Thr](/variant/ids-p-pro261thr), [IDS c.418+1_418+4del](/variant/ids-c-418-plus-1-418-plus-4del), [IDS p.Arg468fs](/variant/ids-p-arg468fs), [IDS p.Arg8fs](/variant/ids-p-arg8fs), [IDS p.Arg96del](/variant/ids-p-arg96del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2737386). 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.*