SF3A3

Chr 1

splicing factor 3a subunit 3

Also known as: PRP9, PRPF9, SAP61, SF3a60

NCBI Gene: 10946 ENSG00000183431 UniProt: Q12874 OMIM: 605596

The protein is a component of the SF3A subcomplex within the U2 snRNP spliceosome, where it participates in pre-mRNA splicing by mediating recognition of intron branch sites and promoting spliceosome assembly. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability, developmental delay, and seizures, typically with onset in infancy or early childhood. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.12), indicating that heterozygous loss is not well tolerated.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes subunit 3 of the splicing factor 3a protein complex. The splicing factor 3a heterotrimer includes subunits 1, 2 and 3 and is necessary for the in vitro conversion of 15S U2 snRNP into an active 17S particle that performs pre-mRNA splicing. Subunit 3 interacts with subunit 1 through its amino-terminus while the zinc finger domain of subunit 3 plays a role in its binding to the 15S U2 snRNP. This gene has a pseudogene on chromosome 20. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.12

Clinical Summary— SF3A3

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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

33 VUS of 58 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 5.70

OE 0.03 (0.01–0.12)

Highly constrained

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

Missense Constraint?

3.62Z-score

OE missense 0.37 (0.32–0.44)

99 obs / 264.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.12)

0≤0.351.4

Missense OE?0.37 (0.32–0.44)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 1 / 39.8Missense obs/exp: 99 / 264.6Syn Z: 0.22

This gene — mechanism propensity

0.2997th %ile

GOF

0.3887th %ile

LOF

0.72top 10%

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

LOFprediction above median · LOEUF 0.12

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

58 submitted variants in ClinVar

ClinVar

Classification Summary

VUS33

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	33	33
Likely Benign	1	1
Benign	0	0
Total	34	34

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap SF3A3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →