# NM_001320752.2(STS):c.1100G>C (p.Trp367Ser)

https://sugi.bio/variant/sts-p-trp367ser

## Summary

**STS p.Trp367Ser (c.1100G>C)** is classified **Uncertain significance** in STS (ClinVar, Single submitter, 2 submitters; last evaluated 2025-05-17). AlphaMissense: likely pathogenic (0.7372); Very rare (popmax 0.000223%, nfe); Associated with recessive X-linked ichthyosis.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs137853168 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000223%, nfe)

## For patients & families {#patients}

This is a change in the STS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to recessive X-linked ichthyosis.

*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) | Neonatal |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | STS is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Recessive X-linked ichthyosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dry skin — Very frequent (99-80%)
- Hyperkeratosis — Very frequent (99-80%)
- Hypohidrosis — Very frequent (99-80%)
- Ichthyosis — Very frequent (99-80%)
- Attention deficit hyperactivity disorder — Frequent (79-30%)
- Opacification of the corneal stroma — Frequent (79-30%)
- Cryptorchidism — Occasional (29-5%)
- Autism — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007904/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STS](https://sugi.bio/atlas/gene/STS/) |
| Protein change (HGVS p.) | p.Trp367Ser |
| Coding change (HGVS c.) | c.1100G>C |
| MANE Select transcript | [NM_001320752](https://www.ncbi.nlm.nih.gov/nuccore/NM_001320752) |
| dbSNP | [rs137853168](https://www.ncbi.nlm.nih.gov/snp/rs137853168/) |
| Variant type | single nucleotide variant |
| Location | chrX:7325357-7325357 (GRCh38) |
| ClinVar | [VCV10555](https://www.ncbi.nlm.nih.gov/clinvar/variation/10555/) |

**All HGVS expressions:** `NC_000023.10:g.7243398G>C`, `NC_000023.11:g.7325357G>C`, `NG_021472.2:g.183106G>C`, `NM_000351.7:c.1100G>C`, `NM_001320750.3:c.1136G>C`, `NM_001320751.2:c.1136G>C`, `NM_001320752.2:c.1100G>C`, `NM_001320753.2:c.1100G>C`, `NM_001320754.2:c.1100G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.7372)
- REVEL 0.886 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.284 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.513, GERP 6.41, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **W372S** vs ClinVar **W367S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.9**. 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 1.16** across the covering region of the MANE Select transcript (7,325,348–7,350,258), spanning 24,910 bp. Chi-square p 0.038. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.34 acceptor loss), 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 **0.000223%** (nfe) · FAF95 3.7e-05% · FAF99 1.4e-05% · 2/895,281 in the highest group · 2/1,211,315 alleles overall — very rare (popmax 0.000223%, 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}

**STS** 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.*

## Protein context {#protein}

Residue **372** lies in a UniProt-annotated variant site (in ixl; loss of steryl-sulfatase activity); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.31, 91% of residues very-high.

**2 experimental structure(s)** (PDB): [1P49](https://www.rcsb.org/structure/1P49), [8EG3](https://www.rcsb.org/structure/8EG3).

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

*Describes the biological roles of STS (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:** STS's established molecular role includes sulfuric ester hydrolase activity.


### Pathways affected {#pathways}

STS participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [Metabolism of steroid hormones](https://reactome.org/content/detail/R-HSA-196071) | curated |
| [The activation of arylsulfatases](https://reactome.org/content/detail/R-HSA-1663150) | curated |

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

**Molecular function:** sulfuric ester hydrolase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-17.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (1997–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1997-08-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-17 |

## Associated conditions {#conditions}

[recessive X-linked ichthyosis](https://sugi.bio/atlas/disease/recessive-x-linked-ichthyosis/).

**Reported phenotype names (ClinVar):** X-linked ichthyosis with steryl-sulfatase deficiency, not provided, none provided, STEROID SULFATASE DEFICIENCY, STEROID SULFATASE DEFICIENCY DISEASE, STS DEFICIENCY, Recessive X-linked ichthyosis, PLACENTAL STEROID SULFATASE DEFICIENCY, Ichthyosis, X-Linked.

## Same-residue context {#hotspot}

Residue **367** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [STS p.Trp367Arg](/variant/sts-p-trp367arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related STS variant pages (same residue, condition, or type): [STS p.Trp367Arg](/variant/sts-p-trp367arg), [STS p.Trp367Cys](/variant/sts-p-trp367cys), [STS p.Gly354Arg](/variant/sts-p-gly354arg), [STS c.383-16C>T](/variant/sts-c-383-minus-16c-t), [STS c.1241+1G>C](/variant/sts-c-1241-plus-1g-c), [STS c.806+1G>A](/variant/sts-c-806-plus-1g-a), [STS p.Gly128Arg](/variant/sts-p-gly128arg), [STS p.Gly370Cys](/variant/sts-p-gly370cys).

### 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 10555). 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.*