FEZF2

Chr 3

FEZ family zinc finger 2

Also known as: FEZ, FEZL, FKSG36, TOF, ZFP312, ZNF312

NCBI Gene: 55079 ENSG00000153266 UniProt: Q8TBJ5 OMIM: 607414

FEZF2 encodes a transcription repressor that specifies corticospinal motor neurons and other subcerebral projection neurons, and controls the development of dendritic arborization and spines of large layer V pyramidal neurons. Mutations cause autosomal dominant developmental and epileptic encephalopathy with microcephaly. The gene is highly constrained against loss-of-function variants (pLI 0.99), indicating that haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable several functions, including DNA-binding transcription factor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and zinc ion binding activity. Predicted to be involved in regulation of gene expression. Predicted to act upstream of or within several processes, including negative regulation of transcription by RNA polymerase II; nervous system development; and regulation of neuron differentiation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.22

Clinical Summary— FEZF2

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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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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 67 VUS of 77 total submissions

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?

0.22LOEUF

pLI 0.989

Z-score 3.40

OE 0.00 (0.00–0.22)

Highly constrained

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

Missense Constraint?

2.07Z-score

OE missense 0.63 (0.55–0.72)

156 obs / 247.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.22)

0≤0.351.4

Missense OE?0.63 (0.55–0.72)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 0 / 13.5Missense obs/exp: 156 / 247.9Syn Z: -1.51

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateFEZF2-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.4090th %ile

GOF

0.3986th %ile

LOF

0.85top 5%

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

LOFprediction above median · 80% of P/LP variants are LoF · LOEUF 0.22

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

77 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS67

Likely Benign2

Benign2

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	2	1	0	0	3
VUS	7	59	1	0	67
Likely Benign	0	1	0	1	2
Benign	0	1	1	0	2
Conflicting	—				1
Total	11	62	2	1	77

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap FEZF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →