# NM_000202.8(IDS):c.727C>T (p.Pro243Ser)

https://sugi.bio/variant/ids-p-pro243ser

## Summary

**IDS p.Pro243Ser (c.727C>T)** is classified **Benign/Likely benign** in IDS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.1329); Ultra-rare (popmax 0.023%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs143474305 · 6 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.023%, nfe)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the IDS gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 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.Pro243Ser |
| Coding change (HGVS c.) | c.727C>T |
| MANE Select transcript | [NM_000202](https://www.ncbi.nlm.nih.gov/nuccore/NM_000202) |
| dbSNP | [rs143474305](https://www.ncbi.nlm.nih.gov/snp/rs143474305/) |
| Variant type | single nucleotide variant |
| Location | chrX:149496498-149496498 (GRCh38) |
| ClinVar | [VCV457355](https://www.ncbi.nlm.nih.gov/clinvar/variation/457355/) |

**All HGVS expressions:** `NC_000023.10:g.148578029G>A`, `NC_000023.11:g.149496498G>A`, `NG_011900.3:g.13837C>T`, `NG_042264.1:g.9853G>A`, `NM_000202.5:c.727C>T`, `NM_000202.7:c.727C>T`, `NM_000202.8:c.727C>T`, `NM_001166550.4:c.457C>T`, `NM_006123.5:c.727C>T`, `NR_104128.2:n.896C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1329)
- REVEL 0.865 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.405 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 11.7, GERP 1.6, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.2**. 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 looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.023%** (nfe) · FAF95 0.0204% · FAF99 0.0194% · 206/895,049 in the highest group · 220/1,209,588 alleles overall — ultra-rare (popmax 0.023%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 1.02% | 98 |
| European (non-Finnish) (grpmax) | 0.023% | 4,345 |
| Remaining individuals (not grpmax-eligible) | 0.00841% | 11,886 |
| South Asian | 0.00352% | 28,416 |
| Finnish (not grpmax-eligible) | 0.00215% | 46,605 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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.*

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-29.

**Submitter consensus:** conflicting (5 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-06-17 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-29 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Mucopolysaccharidosis, MPS-II, not provided, IDS-related disorder, IDS-related condition, Attenuated MPS (subtype; formerly known as mild MPS II), Severe MPS II, I2S deficiency, MPS 2, Hunter Syndrome.

### 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 457355). 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.*