SP4 encodes a transcriptional activator that binds to GT and GC box promoter elements to regulate gene expression. Mutations cause autosomal dominant intellectual disability with speech delay and distinctive facial features, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.28), indicating intolerance to protein-disrupting mutations.

OMIMResearchSummary from UniProt
LOFmechanismLOEUF 0.28
Clinical SummarySP4
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.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.28LOEUF
pLI 0.993
Z-score 4.62
OE 0.12 (0.060.28)
Highly constrained

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

Missense Constraint
0.40Z-score
OE missense 0.94 (0.871.03)
386 obs / 408.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.12 (0.060.28)
00.351.4
Missense OE0.94 (0.871.03)
00.61.4
Synonymous OE1.08
01.21.6
LoF obs/exp: 4 / 32.4Missense obs/exp: 386 / 408.5Syn Z: -0.74
DN
0.3495th %ile
GOF
0.13100th %ile
LOF
0.81top 5%

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

LOFprediction above median · LOEUF 0.28

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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

SP4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
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