ZFPM2

Chr 8AD

zinc finger protein, FOG family member 2

Also known as: DIH3, FOG2, PRDM19, SRXY9, ZC2HC11B, ZNF89B, hFOG-2

NCBI Gene: 23414 ENSG00000169946 UniProt: Q8WW38 OMIM: 603693

This gene encodes a zinc finger transcription factor that acts as an essential cofactor for GATA family proteins, regulating genes critical for heart development and gonadal differentiation. Mutations cause autosomal dominant conditions including tetralogy of Fallot, diaphragmatic hernia, and 46,XY sex reversal, affecting cardiac, pulmonary, and reproductive development. The gene is highly constrained against loss-of-function variants (pLI >0.99), indicating that most protein-disrupting variants are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The zinc finger protein encoded by this gene is a widely expressed member of the FOG family of transcription factors. The family members modulate the activity of GATA family proteins, which are important regulators of hematopoiesis and cardiogenesis in mammals. It has been demonstrated that the protein can both activate and down-regulate expression of GATA-target genes, suggesting different modulation in different promoter contexts. A related mRNA suggests an alternatively spliced product but this information is not yet fully supported by the sequence. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.143 OMIM phenotypes

Clinical Summary— ZFPM2

⚡

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.

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?

0.14LOEUF

pLI 1.000

Z-score 5.82

OE 0.05 (0.02–0.14)

Highly constrained

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

Missense Constraint?

0.21Z-score

OE missense 0.98 (0.91–1.04)

581 obs / 595.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.14)

0≤0.351.4

Missense OE?0.98 (0.91–1.04)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 2 / 43.3Missense obs/exp: 581 / 595.6Syn Z: 0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedZFPM2-related malformation syndromeOTHERAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.1999th %ile

LOF

0.83top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.14

Literature Evidence

LOFThe same variant is seen in 2 additional family members, both of whom are asymptomatic, thus highlighting that ZFPM2 haploinsufficiency is associated with reduced penetrance.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References