SP9

Chr 2

Sp9 transcription factor

Also known as: ZNF990

NCBI Gene: 100131390 ENSG00000217236 UniProt: P0CG40 OMIM: 621003

This transcription factor regulates FGF8 expression during limb development and is essential for proper limb outgrowth during embryogenesis. Mutations cause autosomal dominant limb defects and developmental abnormalities affecting the extremities. The gene is highly constrained against loss-of-function variants (pLI 0.94, LOEUF 0.34), indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, UniProt

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.34

Clinical Summary— SP9

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 61 VUS of 70 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.940

Z-score 2.77

OE 0.00 (0.00–0.34)

Highly constrained

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

Missense Constraint?

2.26Z-score

OE missense 0.55 (0.47–0.64)

107 obs / 196.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.34)

0≤0.351.4

Missense OE?0.55 (0.47–0.64)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 0 / 8.9Missense obs/exp: 107 / 196.3Syn Z: 0.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateSP9-related neurodevelopmental disorder with or without epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.4685th %ile

GOF

0.2398th %ile

LOF

0.88top 5%

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

LOFprediction above median · 67% of P/LP variants are LoF · LOEUF 0.34

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

70 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS61

Likely Benign3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	3	1	0	4
Likely Pathogenic	1	1	0	2
VUS	0	61	0	61
Likely Benign	0	0	3	3
Benign	0	0	0	0
Total	4	63	3	70

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap SP9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →