# NM_000202.8(IDS):c.666C>T (p.Ala222=)

https://sugi.bio/variant/ids-p-ala222

## Summary

**IDS p.Ala222= (c.666C>T)** is classified **Benign** in IDS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-17). Rare (popmax 0.24%, eas); Associated with Inborn genetic diseases.

**At a glance:** Benign · review: Multiple submitters · rsID rs201588028 · 5 submitters · 3 linked conditions · rare (popmax 0.24%, eas)

## For patients & families {#patients}

This is a change in the IDS gene that is classified as benign — not considered disease-causing, submitted by 5 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Ala222= |
| Coding change (HGVS c.) | c.666C>T |
| MANE Select transcript | [NM_000202](https://www.ncbi.nlm.nih.gov/nuccore/NM_000202) |
| dbSNP | [rs201588028](https://www.ncbi.nlm.nih.gov/snp/rs201588028/) |
| Variant type | single nucleotide variant |
| Location | chrX:149498149-149498149 (GRCh38) |
| ClinVar | [VCV697822](https://www.ncbi.nlm.nih.gov/clinvar/variation/697822/) |

**All HGVS expressions:** `NC_000023.10:g.148579680G>A`, `NC_000023.11:g.149498149G>A`, `NG_011900.3:g.12186C>T`, `NG_042264.1:g.11504G>A`, `NM_000202.5:c.666C>T`, `NM_000202.7:c.666C>T`, `NM_000202.8:c.666C>T`, `NM_001166550.4:c.396C>T`, `NM_006123.5:c.666C>T`, `NR_104128.2:n.835C>T`

## 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 -1.591, GERP -2.86 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.783**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.22 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.24%** (eas) · FAF95 0.198% · FAF99 0.182% · 81/33,747 in the highest group · 588/1,209,697 alleles overall — rare (popmax 0.24%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.24% | 417 |
| Finnish (not grpmax-eligible) | 0.0902% | 1,109 |
| Remaining individuals (not grpmax-eligible) | 0.0504% | 1,983 |
| European (non-Finnish) | 0.0487% | 2,053 |
| African / African-American | 0.00525% | 19,036 |
| Admixed American | 0.00218% | 45,834 |
| South Asian | 0.00176% | 56,807 |

*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 **222** lies in a β-strand.

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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-17.

**Submitter consensus:** conflicting (3 Benign, 2 Likely benign).

**Submission history:** 5 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-03-12 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2017-11-29 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-09-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-17 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-10-30 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [mucopolysaccharidosis type 3A](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-3a/), [mucopolysaccharidosis type 2](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-2/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Mucopolysaccharidosis, MPS-II, Mucopolysaccharidosis, MPS-III-A, IDS-related disorder, not specified, IDS-related condition, HEPARAN SULFATE SULFATASE DEFICIENCY, SANFILIPPO SYNDROME A, SULFAMIDASE DEFICIENCY, MUCOPOLYSACCHARIDOSIS, TYPE IIIA, ATTENUATED.

## Similar variants {#similar}

Related IDS variant pages (same residue, condition, or type): [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), [IDS c.103+1G>A](/variant/ids-c-103-plus-1g-a), [IDS c.104-2A>G](/variant/ids-c-104-minus-2a-g).

### 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 697822). 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.*