# NM_003036.4(SKI):c.1150C>T (p.Pro384Ser)

https://sugi.bio/variant/ski-p-pro384ser

## Summary

**SKI p.Pro384Ser (c.1150C>T)** is classified **Uncertain significance** in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-09). AlphaMissense: likely pathogenic (0.7199); Very rare (popmax 0.0011%, sas); Associated with Shprintzen-Goldberg syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1242691039 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the SKI gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Shprintzen-Goldberg syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004861/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SKI](https://sugi.bio/atlas/gene/SKI/) |
| Protein change (HGVS p.) | p.Pro384Ser |
| Coding change (HGVS c.) | c.1150C>T |
| MANE Select transcript | [NM_003036](https://www.ncbi.nlm.nih.gov/nuccore/NM_003036) |
| dbSNP | [rs1242691039](https://www.ncbi.nlm.nih.gov/snp/rs1242691039/) |
| Variant type | single nucleotide variant |
| Location | chr1:2303339-2303339 (GRCh38) |
| ClinVar | [VCV1014555](https://www.ncbi.nlm.nih.gov/clinvar/variation/1014555/) |

**All HGVS expressions:** `NC_000001.10:g.2234778C>T`, `NC_000001.11:g.2303339C>T`, `NG_013084.1:g.79645C>T`, `NM_003036.4:c.1150C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7199)
- REVEL 0.642 (indeterminate)
- SaProt LLR -6.161 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 7.492, GERP 1.56, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.2**. 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 1.10** across the covering region of the MANE Select transcript (2,229,630–2,306,762), spanning 77,132 bp. Chi-square p 0.0098. 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 **0.0011%** (sas) · 1/91,088 in the highest group · 1/1,613,898 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**SKI** population constraint: LOEUF 0.809, pLI 6.9663e-06, missense-Z -1.1759; ClinGen dosage — haploinsufficiency 0/3, 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):

- **Shprintzen-Goldberg syndrome** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 67.18, 37% of residues very-high.

**4 experimental structure(s)** (PDB): [1MR1](https://www.rcsb.org/structure/1MR1), [1SBX](https://www.rcsb.org/structure/1SBX), [5XOD](https://www.rcsb.org/structure/5XOD), [6ZVQ](https://www.rcsb.org/structure/6ZVQ).

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

*Describes the biological roles of SKI (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:** SKI's established molecular role includes DNA-binding transcription repressor activity, RNA polymerase II-specific.


### Pathways affected {#pathways}

SKI participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signaling by BMP](https://reactome.org/content/detail/R-HSA-201451) | curated |
| [Downregulation of SMAD2/3:SMAD4 transcriptional activity](https://reactome.org/content/detail/R-HSA-2173795) | electronic |

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

**Molecular function:** DNA-binding transcription repressor activity, RNA polymerase II-specific, zinc ion binding, protein kinase binding, protein domain specific binding, ubiquitin protein ligase binding, identical protein binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, negative regulation of cell population proliferation, negative regulation of Schwann cell proliferation, myotube differentiation, negative regulation of transforming growth factor beta receptor signaling pathway, negative regulation of BMP signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-09-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-09-09 |

## Associated conditions {#conditions}

[Shprintzen-Goldberg syndrome](https://sugi.bio/atlas/disease/shprintzen-goldberg-syndrome/).

**Reported phenotype names (ClinVar):** Shprintzen-Goldberg syndrome, SHPRINTZEN-GOLDBERG CRANIOSYNOSTOSIS SYNDROME, CRANIOSYNOSTOSIS WITH ARACHNODACTYLY AND ABDOMINAL HERNIAS, Marfanoid disorder with craniosynostosis type 1, Marfanoid craniosynostosis syndrome, Shprintzen-Goldberg marfanoid syndrome.

## Similar variants {#similar}

Related SKI variant pages (same residue, condition, or type): [SKI p.Pro384=](/variant/ski-p-pro384), [SKI p.Gly116Glu](/variant/ski-p-gly116glu), [SKI p.Gly117Arg](/variant/ski-p-gly117arg), [SKI p.Gly117Ser](/variant/ski-p-gly117ser), [SKI p.Gly34Cys](/variant/ski-p-gly34cys), [SKI p.Gly34Ser](/variant/ski-p-gly34ser), [SKI p.Gly34Val](/variant/ski-p-gly34val), [SKI p.Leu32Val](/variant/ski-p-leu32val).

### 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 1014555). 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.*