# NM_000202.8(IDS):c.1417C>T (p.Pro473Ser)

https://sugi.bio/variant/ids-p-pro473ser

## Summary

**IDS p.Pro473Ser (c.1417C>T)** is classified **Uncertain significance** in IDS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-08). AlphaMissense: ambiguous (0.5305); Very rare (popmax 0.000335%, nfe); Associated with mucopolysaccharidosis type 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2123994315 · 4 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.000335%, nfe)

## For patients & families {#patients}

This is a change in the IDS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 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.Pro473Ser |
| Coding change (HGVS c.) | c.1417C>T |
| MANE Select transcript | [NM_000202](https://www.ncbi.nlm.nih.gov/nuccore/NM_000202) |
| dbSNP | [rs2123994315](https://www.ncbi.nlm.nih.gov/snp/rs2123994315/) |
| Variant type | single nucleotide variant |
| Location | chrX:149482982-149482982 (GRCh38) |
| ClinVar | [VCV1186178](https://www.ncbi.nlm.nih.gov/clinvar/variation/1186178/) |

**All HGVS expressions:** `NC_000023.10:g.148564513G>A`, `NC_000023.11:g.149482982G>A`, `NG_011900.3:g.27353C>T`, `NM_000202.8:c.1417C>T`, `NM_001166550.4:c.1147C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5305) — no call either way
- REVEL 0.763 (pathogenic-leaning)
- SaProt LLR -7.93 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 11.777, GERP 1.59, phastCons 1 — highly conserved
- CADD: **PHRED 23.1**. 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 0.78** across the covering region of the MANE Select transcript (149,482,749–149,503,339), spanning 20,590 bp. Chi-square p 5.6e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000335%** (nfe) · FAF95 8.9e-05% · FAF99 2.5e-05% · 3/894,741 in the highest group · 3/1,210,997 alleles overall — very rare (popmax 0.000335%, 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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-08.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 not provided).

**Submission history:** 4 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-08 |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-04-16 |

## 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, Mucopolysaccharidosis with skin involvement, IDS deficiency, Sulfoiduronate sulfatase deficiency, SIDS deficiency, Mucopolysaccharidosis Type II, Mucopolysaccharidosis type 2, Attenuated MPS (subtype; formerly known as mild MPS II).

## Same-residue context {#hotspot}

Residue **473** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [IDS p.Pro473fs](/variant/ids-p-pro473fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related IDS variant pages (same residue, condition, or type): [IDS p.Pro473Leu](/variant/ids-p-pro473leu), [IDS p.Pro473fs](/variant/ids-p-pro473fs), [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), [IDS c.1007-2A>C](/variant/ids-c-1007-minus-2a-c), [IDS c.1007-8T>G](/variant/ids-c-1007-minus-8t-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 1186178). 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.*