SUFU

Chr 10ADARSomatic

SUFU negative regulator of hedgehog signaling

NCBI Gene: 51684ENSG00000107882UniProt: Q9UMX1

Negative regulator in the hedgehog/smoothened signaling pathway (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:12068298, PubMed:12975309, PubMed:15367681, PubMed:22365972, PubMed:24217340, PubMed:24311597, PubMed:27234298, PubMed:28965847). Down-regulates GLI1-mediated transactivation of target genes (PubMed:15367681, PubMed:24217340, PubMed:24311597). Down-regulates GLI2-mediated transactivation of target genes (PubMed:24217340, PubMed:24311597). Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340). Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340). Negative regulator of beta-catenin signaling (By similarity). Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full-length form of GLI3 (GLI3FL) (PubMed:24311597, PubMed:28965847). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state (PubMed:24311597, PubMed:28965847). Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R (PubMed:24311597, PubMed:28965847). When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A) (PubMed:24311597, PubMed:28965847). Required for normal embryonic development (By similarity). Required for the proper formation of hair follicles and the control of epidermal differentiation (By similarity)

Primary Disease Associations & Inheritance

{Medulloblastoma}MIM #155255
ADARSomatic
{Meningioma, familial, susceptibility to}MIM #607174
AD
Basal cell nevus syndrome 2MIM #620343
Joubert syndrome 32MIM #617757
AR
587
ClinVar variants
46
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SUFU
🧬
Gene-Disease Validity (ClinGen)
medulloblastoma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 325 VUS of 587 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.93Z-score
OE missense 0.68 (0.60–0.76)
194 obs / 286.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.60–0.76)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92
0≤1.21.6
LoF obs/exp: 0 / 26.9Missense obs/exp: 194 / 286.0Syn Z: 0.72

ClinVar Variant Classifications

587 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic14
VUS325
Likely Benign210
Conflicting6
32
Pathogenic
14
Likely Pathogenic
325
VUS
210
Likely Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
0
19
0
32
Likely Pathogenic
13
0
1
0
14
VUS
7
284
33
1
325
Likely Benign
0
3
99
108
210
Benign
0
0
0
0
0
Conflicting
—6
Total33287152109587

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

View in ClinVar →

Protein Context — Lollipop Plot

SUFU · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SUFU-related Joubert syndrome with cranio-facial and skeletal defects

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

SUFU-related basal cell nevus syndrome

strong
ADUndeterminedAbsent Gene Product
Skin
G2P ↗

SUFU-related medulloblastoma, associated with Gorlin syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Cancer
G2P ↗

SUFU-related Joubert and congenital ocular motor apraxia

strong
ADUndeterminedAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Medulloblastoma}

MIM #155255

Molecular basis of disorder known

Autosomal dominantAutosomal recessiveSomatic mutation

{Meningioma, familial, susceptibility to}

MIM #607174

Molecular basis of disorder known

Autosomal dominant

Basal cell nevus syndrome 2

MIM #620343

Molecular basis of disorder known

Joubert syndrome 32

MIM #617757

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SUFU
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline.
Anger J et al.·J Urol
2019Guideline
Updates to Microhematuria: AUA/SUFU Guideline (2025).
Barocas DA et al.·J Urol
2025Guideline
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.
Kim J et al.·JNCI Cancer Spectr
2021
Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline Amendment 2019.
Lightner DJ et al.·J Urol
2019Guideline
Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis.
Louvrier C et al.·Neuro Oncol
2018
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.
Waszak SM et al.·Lancet Oncol
2018Cohort
Updates to Surgical Treatment of Female Stress Urinary Incontinence (SUI): AUA/SUFU Guideline (2023).
Kobashi KC et al.·J Urol
2023Guideline
European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection.
Sahm F et al.·Neuro Oncol
2025Review
Inherited Basaloid Neoplasms Associated With SUFU Pathogenic Variants.
Abbott JJ et al.·JAMA Dermatol
2024
Medulloblastoma and other neoplasms in patients with heterozygous germline SUFU variants: A scoping review.
Lee SG et al.·Am J Med Genet A
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools