SF3B4

Chr 1AD

splicing factor 3b subunit 4

Also known as: AFD1, Hsh49, SAP49, SF3b49

NCBI Gene: 10262ENSG00000143368UniProt: Q15427

This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Acrofacial dysostosis 1, Nager typeMIM #154400
AD
164
ClinVar variants
57
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SF3B4
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Gene-Disease Validity (ClinGen)
SF3B4-related acrofacial dysostosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 51 VUS of 164 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.21LOEUF
pLI 0.992
Z-score 3.51
OE 0.00 (0.00–0.21)
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.
3.87Z-score
OE missense 0.29 (0.24–0.36)
70 obs / 237.8 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.0.00 (0.00–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.29 (0.24–0.36)
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.1.09
0≤1.21.6
LoF obs/exp: 0 / 14.4Missense obs/exp: 70 / 237.8Syn Z: -0.65

ClinVar Variant Classifications

164 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51
Likely Pathogenic6
VUS51
Likely Benign35
Benign17
Conflicting4
51
Pathogenic
6
Likely Pathogenic
51
VUS
35
Likely Benign
17
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
28
2
20
1
51
Likely Pathogenic
5
0
1
0
6
VUS
0
39
9
3
51
Likely Benign
0
5
3
27
35
Benign
0
0
13
4
17
Conflicting
—4
Total33464635164

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

View in ClinVar →

Protein Context — Lollipop Plot

SF3B4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SF3B4-related acrofacial dysostosis, Nager type

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Acrofacial dysostosis 1, Nager type

MIM #154400

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genome-wide CRISPR screen identifies splicing factor SF3B4 in driving hepatocellular carcinoma.
Guo Y et al.·Sci Adv
2025
Alternative splicing in ovarian cancer.
Wei L et al.·Cell Commun Signal
2024Review
Sf3b4 regulates chromatin remodeler splicing and Hox expression.
Kumar S et al.·Differentiation
2023Functional
Exosomal transfer of pro-pyroptotic miR-216a-5p exacerbates anthracycline cardiotoxicity through breast cancer-heart pathological crosstalk.
Ma Y et al.·Signal Transduct Target Ther
2025
SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome.
Ulhaq ZS et al.·Cleft Palate Craniofac J
2023
SF3B4 is regulated by microRNA-133b and promotes cell proliferation and metastasis in hepatocellular carcinoma.
Liu Z et al.·EBioMedicine
2018
SF3B4 Plays an Oncogenic Role in Esophageal Squamous Cell Carcinoma.
Kidogami S et al.·Anticancer Res
2020
Children with Rare Nager Syndrome-Literature Review, Clinical and Physiotherapeutic Management.
Marszałek-Kruk BA et al.·Genes (Basel)
2023Review
Etiology of craniofacial and cardiac malformations in a mouse model of SF3B4-related syndromes.
Kumar S et al.·Proc Natl Acad Sci U S A
2024Functional
Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination.
Qin J et al.·WIREs Mech Dis
2026Review
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