TFAP4

Chr 16

transcription factor AP-4

Also known as: AP-4, bHLHc41

NCBI Gene: 7023 ENSG00000090447 UniProt: Q01664 OMIM: 600743

Transcription factor AP4 is a basic helix-loop-helix-zipper transcription factor that activates viral and cellular genes by binding to the symmetrical DNA sequence 5'-CAGCTG-3'. Mutations cause autosomal dominant developmental and epileptic encephalopathy with microcephaly. This gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Transcription factors of the basic helix-loop-helix-zipper (bHLH-ZIP) family contain a basic domain, which is used for DNA binding, and HLH and ZIP domains, which are used for oligomerization. Transcription factor AP4 activates both viral and cellular genes by binding to the symmetrical DNA sequence CAGCTG (Mermod et al., 1988 [PubMed 2833704]; Hu et al., 1990 [PubMed 2123466]).[supplied by OMIM, Jul 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.17

Clinical Summary— TFAP4

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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

34 VUS of 48 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 0.997

Z-score 3.86

OE 0.00 (0.00–0.17)

Highly constrained

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

Missense Constraint?

1.60Z-score

OE missense 0.70 (0.61–0.80)

152 obs / 218.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.70 (0.61–0.80)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 0 / 17.4Missense obs/exp: 152 / 218.4Syn Z: -0.28

This gene — mechanism propensity

0.3396th %ile

GOF

0.2597th %ile

LOF

0.82top 5%

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

LOFprediction above median · LOEUF 0.17

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

48 submitted variants in ClinVar

ClinVar

Classification Summary

VUS34

Benign1

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	34	34
Likely Benign	0	0
Benign	1	1
Total	35	35

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap TFAP4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →