SKI

Chr 1AD

SKI proto-oncogene

ENSG00000157933 UniProt: P12755 OMIM: 164780

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).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Functions as a repressor of TGF-beta signaling

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— SKI

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Gene-Disease Validity (ClinGen)

Shprintzen-Goldberg syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSKI-related Shprintzen-Goldberg craniosynostosis syndromeOTHERAD

This gene — mechanism propensity

0.3097th %ile

GOF

0.3293th %ile

LOF

0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.19

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.