SKI

Chr 1

SKI proto-oncogene

Also known as: SGS, SKV

NCBI Gene: 6497 ENSG00000157933 UniProt: P12755

The SKI protein functions as a repressor of TGF-beta signaling and plays a role in neural tube development and muscle differentiation. Mutations cause Shprintzen-Goldberg syndrome, a connective tissue disorder with craniosynostosis, arachnodactyly, and intellectual disability. This gene follows autosomal dominant inheritance and is highly constrained against loss-of-function mutations (pLI 0.999).

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the nuclear protooncogene protein homolog of avian sarcoma viral (v-ski) oncogene. It functions as a repressor of TGF-beta signaling, and may play a role in neural tube development and muscle differentiation. [provided by RefSeq, Oct 2009]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtShprintzen-Goldberg craniosynostosis syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Shprintzen-Goldberg syndrome · AD · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

332

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

LOF

Mechanism· predicted

📖

GeneReview available — SKI

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.40

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.51Z-score

OE missense 0.80 (0.73–0.87)

349 obs / 438.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.80 (0.73–0.87)

0≤0.61.4

Synonymous OE?1.43

0≤1.21.6

LoF obs/exp: 1 / 24.5Missense obs/exp: 349 / 438.2Syn Z: -4.87

Background carrier burden — how many people carry a rare variant somewhere in SKI?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 67

1,083 rare PASS variants

Rare truncating (LoF)

1 in 3,400

66 rare PASS variants

Rare synonymous (reference)

1 in 60

711 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SKI. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 5,400
South Asian	~43k	1 in 65	1 in 800
Remaining (unassigned)	~30k	1 in 63	1 in 5,800
European (Finnish)	~27k	1 in 140	1 in 1,800
Admixed American	~22k	1 in 66	1 in 1,600
African / African American	~21k	1 in 52	≈ 1 in 4,300
East Asian	~20k	1 in 92	≈ 1 in 4,500
Ashkenazi Jewish	~13k	1 in 440	≈ 1 in 2,700
Middle Eastern	~2,884	1 in 63	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓