# NM_003036.4(SKI):c.1967C>T (p.Ala656Val)

https://sugi.bio/variant/ski-p-ala656val

## Summary

**SKI p.Ala656Val (c.1967C>T)** is classified **Conflicting classifications of pathogenicity** in SKI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: ambiguous (0.4882); Very rare (popmax 0.00677%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs571976990 · 2 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00677%, afr)

## For patients & families {#patients}

This is a change in the SKI gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to familial thoracic aortic aneurysm and aortic dissection.

*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) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SKI is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002249/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.Ala656Val |
| Coding change (HGVS c.) | c.1967C>T |
| MANE Select transcript | [NM_003036](https://www.ncbi.nlm.nih.gov/nuccore/NM_003036) |
| dbSNP | [rs571976990](https://www.ncbi.nlm.nih.gov/snp/rs571976990/) |
| Variant type | single nucleotide variant |
| Location | chr1:2306219-2306219 (GRCh38) |
| ClinVar | [VCV463402](https://www.ncbi.nlm.nih.gov/clinvar/variation/463402/) |

**All HGVS expressions:** `NC_000001.10:g.2237658C>T`, `NC_000001.11:g.2306219C>T`, `NG_013084.1:g.82525C>T`, `NM_003036.4:c.1967C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4882) — no call either way
- REVEL 0.663 (pathogenic-leaning)
- SaProt LLR -5.833 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.82) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.45, GERP 1.77, phastCons 1 — highly conserved
- CADD: **PHRED 34.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.82**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.82**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.01. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00677%** (afr) · FAF95 0.00258% · FAF99 0.00164% · 5/73,890 in the highest group · 16/1,565,490 alleles overall — very rare (popmax 0.00677%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00677% | 14,778 |
| Admixed American | 0.00381% | 26,265 |
| South Asian | 0.00117% | 85,410 |
| European (non-Finnish) | 0.000692% | 144,517 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-27.

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

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-11 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-27 |

## Associated conditions {#conditions}

[familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/), [Shprintzen-Goldberg syndrome](https://sugi.bio/atlas/disease/shprintzen-goldberg-syndrome/).

**Reported phenotype names (ClinVar):** Familial thoracic aortic aneurysm and aortic dissection, Shprintzen-Goldberg syndrome, Thoracic aortic aneurysms and dissections, CRANIOSYNOSTOSIS WITH ARACHNODACTYLY AND ABDOMINAL HERNIAS, Marfanoid disorder with craniosynostosis type 1, Marfanoid craniosynostosis syndrome, Shprintzen-Goldberg marfanoid syndrome, SHPRINTZEN-GOLDBERG CRANIOSYNOSTOSIS SYNDROME.

## Similar variants {#similar}

Related SKI variant pages (same residue, condition, or type): [SKI p.Ala656=](/variant/ski-p-ala656), [SKI p.Ala656delinsValProAlaGlyLysAlaLeuGluGlnLysProGlyProGlyProArgSerValArgAlaProProThr](/variant/ski-p-ala656delinsvalproalaglylysalaleugluglnlysproglyproglypro-d0a819cc), [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).

### 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 463402). 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.*