SUFU

Chr 10

SUFU negative regulator of hedgehog signaling

Also known as: BCNS2, JBTS32, PRO1280, SUFUH, SUFUXL

NCBI Gene: 51684 ENSG00000107882 UniProt: Q9UMX1

The protein functions as a negative regulator of the Hedgehog signaling pathway, which controls pattern formation and cellular proliferation during development. Loss-of-function mutations cause autosomal dominant basal cell nevus syndrome 2 and medulloblastoma susceptibility, autosomal recessive Joubert syndrome 32, and somatic mutations contribute to sporadic medulloepitheliomas and meningiomas. The gene is highly intolerant to loss-of-function variation, reflecting its critical role in developmental regulation.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.11

Clinical Summary— SUFU

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Gene-Disease Validity (ClinGen)

medulloblastoma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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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ClinVar Variants

128 unique Pathogenic / Likely Pathogenic· 864 VUS of 1831 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SUFU

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?

0.11LOEUF

pLI 1.000

Z-score 4.80

OE 0.00 (0.00–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.93Z-score

OE missense 0.68 (0.60–0.76)

194 obs / 286.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.11)

0≤0.351.4

Missense OE?0.68 (0.60–0.76)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 0 / 26.9Missense obs/exp: 194 / 286.0Syn Z: 0.72

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSUFU-related Joubert syndrome with cranio-facial and skeletal defectsOTHERAR

strongSUFU-related basal cell nevus syndromeOTHERAD

definitiveSUFU-related medulloblastoma, associated with Gorlin syndromeLOFAD

strongSUFU-related Joubert and congenital ocular motor apraxiaOTHERAD

This gene — mechanism propensity

0.3097th %ile

GOF

0.4776th %ile

LOF

0.69top 10%

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

LOFprediction above median · 1 literature citation · 88% of P/LP variants are LoF · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFSUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.1

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

References

1.PMID 34675124 ↗

ClinVar Variant Classifications

1831 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic89

Likely Pathogenic39

VUS864

Likely Benign681

Benign34

Conflicting109

Pathogenic

Likely Pathogenic

864

VUS

681

Likely Benign

Benign

109

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	79	1	9	0	89
Likely Pathogenic	33	1	5	0	39
VUS	13	750	94	7	864
Likely Benign	0	9	260	412	681
Benign	0	0	33	1	34
Conflicting	—				109
Total	125	761	401	420	1,816

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap SUFU — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →