# NM_004595.5(SMS):c.171C>T (p.Ser57=)

https://sugi.bio/variant/sms-p-ser57

## Summary

**SMS p.Ser57= (c.171C>T)** is classified **Benign/Likely benign** in SMS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-10-25). Ultra-rare (popmax 0.0331%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs201558273 · 6 submitters · 2 linked conditions · ultra-rare (popmax 0.0331%, nfe)

## For patients & families {#patients}

This is a change in the SMS 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 | [SMS](https://sugi.bio/atlas/gene/SMS/) |
| Protein change (HGVS p.) | p.Ser57= |
| Coding change (HGVS c.) | c.171C>T |
| MANE Select transcript | [NM_004595](https://www.ncbi.nlm.nih.gov/nuccore/NM_004595) |
| dbSNP | [rs201558273](https://www.ncbi.nlm.nih.gov/snp/rs201558273/) |
| Variant type | single nucleotide variant |
| Location | chrX:21971897-21971897 (GRCh38) |
| ClinVar | [VCV728106](https://www.ncbi.nlm.nih.gov/clinvar/variation/728106/) |

**All HGVS expressions:** `NC_000023.10:g.21990015C>T`, `NC_000023.11:g.21971897C>T`, `NG_009228.1:g.36174C>T`, `NM_001258423.2:c.170+4581C>T`, `NM_004595.5:c.171C>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 1.721, GERP 1.31, phastCons 1 — weakly conserved position
- CADD: **PHRED 15.08**. 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 (C>G, Δ0.26 acceptor 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 **0.0331%** (nfe) · FAF95 0.0299% · FAF99 0.0286% · 285/861,571 in the highest group · 299/1,171,026 alleles overall — ultra-rare (popmax 0.0331%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0331% | 3,023 |
| Remaining individuals (not grpmax-eligible) | 0.0173% | 5,785 |
| African / African-American | 0.0107% | 9,335 |

*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}

**SMS** 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):

- **syndromic X-linked intellectual disability Snyder type** — Definitive (XL)

## Protein context {#protein}

Residue **57** lies in a modified residue (phosphoserine).

AlphaFold model confidence (whole protein): pLDDT 95.09, 89% of residues very-high.

**2 experimental structure(s)** (PDB): [3C6K](https://www.rcsb.org/structure/3C6K), [3C6M](https://www.rcsb.org/structure/3C6M).

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

*Describes the biological roles of SMS (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:** SMS's established molecular role includes spermine synthase activity.


### Pathways affected {#pathways}

SMS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Metabolism of polyamines](https://reactome.org/content/detail/R-HSA-351202) | curated |

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

**Molecular function:** spermine synthase activity.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-25.

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

**Submission history:** 6 submissions (2017–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2017-09-21 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Benign | criteria provided, single submitter | clinical testing | 2019-04-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2024-10-25 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-28 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Intellectual disability, not specified, AllHighlyPenetrant, Intellectual functioning disability, Intellectual developmental disorder, intellectual disabilities, none provided.

## Similar variants {#similar}

Related SMS variant pages (same residue, condition, or type): [SMS p.Arg234Ter](/variant/sms-p-arg234ter), [SMS p.Gly56Ser](/variant/sms-p-gly56ser), [SMS p.Pro112Leu](/variant/sms-p-pro112leu), [SMS p.Lys245Asn](/variant/sms-p-lys245asn), [SMS p.Ser184Asn](/variant/sms-p-ser184asn), [SMS p.Ala36Val](/variant/sms-p-ala36val), [SMS p.Glu187=](/variant/sms-p-glu187), [SMS p.Pro281=](/variant/sms-p-pro281).

### 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 728106). 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.*