SF1

Chr 11

splicing factor 1

Also known as: BBP, D11S636, MBBP, ZCCHC25, ZFM1, ZNF162

NCBI Gene: 7536ENSG00000168066UniProt: Q13285

This gene encodes a nuclear pre-mRNA splicing factor. The encoded protein specifically recognizes the intron branch point sequence at the 3' splice site, together with the large subunit of U2 auxiliary factor (U2AF), and is required for the early stages of spliceosome assembly. It also plays a role in nuclear pre-mRNA retention and transcriptional repression. The encoded protein contains an N-terminal U2AF ligand motif, a central hnRNP K homology motif and quaking 2 region which bind a key branch-site adenosine within the branch point sequence, a zinc knuckles domain, and a C-terminal proline-rich domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

Primary Disease Associations & Inheritance

UniProt46,XY sex reversal 3
UniProt46,XX sex reversal 4
UniProtAdrenal insufficiency, NR5A1-related
UniProtPremature ovarian failure 7
116
ClinVar variants
11
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SF1
⚡
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
11 Pathogenic / Likely Pathogenic· 94 VUS of 116 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.18LOEUF
pLI 0.999
Z-score 4.54
OE 0.04 (0.01–0.18)
Highly constrained

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

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.
3.62Z-score
OE missense 0.45 (0.39–0.51)
151 obs / 338.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.04 (0.01–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.45 (0.39–0.51)
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.1.26
0≤1.21.6
LoF obs/exp: 1 / 25.9Missense obs/exp: 151 / 338.4Syn Z: -2.27

ClinVar Variant Classifications

116 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic4
VUS94
Likely Benign11
7
Pathogenic
4
Likely Pathogenic
94
VUS
11
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
7
0
7
Likely Pathogenic
2
0
2
0
4
VUS
1
88
5
0
94
Likely Benign
0
11
0
0
11
Benign
0
0
0
0
0
Total399140116

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

View in ClinVar →

Protein Context — Lollipop Plot

SF1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SF1-related neurodevelopmental disorder

moderate
ADLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗
frameshift variantmissense variantinframe deletionintron variantstop gained NMD escaping

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SPLICING FACTOR 1; SF1
MIM #601516 · *
📖
GeneReview available — SF1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Overview of the 2022 WHO Classification of Pituitary Tumors.
Asa SL et al.·Endocr Pathol
2022Review
Pangenomic Classification of Pituitary Neuroendocrine Tumors.
Neou M et al.·Cancer Cell
2020
PCOS and Inositols - Advances and Lessons We are Learning. A Narrative Review.
Lentini G et al.·Drug Des Devel Ther
2025Review
Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK.
Greenwood SA et al.·Lancet Digit Health
2024
Efficacy of digestive enzyme supplementation in functional dyspepsia: A monocentric, randomized, double-blind, placebo-controlled, clinical trial.
Ullah H et al.·Biomed Pharmacother
2023Functional
SF1 in the development of the adrenal gland and gonads.
Ozisik G et al.·Horm Res
2003Review
Broader impact and outcome of human NR5A1/SF1 variants.
Kouri C et al.·Best Pract Res Clin Endocrinol Metab
2025Review
Pituitary neuroendocrine tumors with PIT1/SF1 co-expression show distinct clinicopathological and molecular features.
Dottermusch M et al.·Acta Neuropathol
2024Meta-analysis
Single-Cell Atlas Reveals Tumorigenic Profiles and Immune Dynamics of Adrenal Incidentalomas.
Wang M et al.·Adv Sci (Weinh)
2025
Skull Base Tumors: Neuropathology and Clinical Implications.
Bi WL et al.·Neurosurgery
2022Review
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