SKOR2

Chr 18AR

SKI family transcriptional corepressor 2

Also known as: CH18515, CORL2, FUSSEL18, VAFCAS

NCBI Gene: 652991 ENSG00000215474 UniProt: Q2VWA4 OMIM: 617138

SKOR2 encodes a transcriptional repressor that binds SMAD proteins and negatively regulates TGF-beta signaling in the nervous system. Mutations cause Valence-Farazi cerebellar ataxia syndrome with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.436), consistent with its essential role in cerebellar development and function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables SMAD binding activity and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transforming growth factor beta receptor signaling pathway. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.441 OMIM phenotype

Clinical Summary— SKOR2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.75) — some intolerance to loss-of-function variants.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic of 8 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.754

Z-score 3.25

OE 0.17 (0.08–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.63Z-score

OE missense 0.72 (0.64–0.81)

193 obs / 268.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.08–0.44)

0≤0.351.4

Missense OE?0.72 (0.64–0.81)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 3 / 17.8Missense obs/exp: 193 / 268.2Syn Z: -1.09

This gene — mechanism propensity

0.4190th %ile

GOF

0.3590th %ile

LOF

0.80top 5%

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

LOFprediction above median · 40% of P/LP variants are LoF · LOEUF 0.44

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

ClinVar Variant Classifications

8 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Pathogenic

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	2	1	2	5
Likely Pathogenic	0	0	0	0
VUS	0	0	0	0
Likely Benign	0	0	0	0
Benign	0	0	0	0
Total	2	1	2	5

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

42 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap SKOR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →