CREBZF

Chr 11

CREB/ATF bZIP transcription factor

Also known as: SMILE, ZF

NCBI Gene: 58487 ENSG00000137504 UniProt: Q9NS37 OMIM: 606444

CREBZF encodes a transcriptional regulator that activates transcription when bound to HCFC1 and suppresses viral protein expression during HSV infection. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, seizures, and distinctive facial features. The gene shows tolerance to loss-of-function variants (pLI 0.10, LOEUF 0.86), consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Enables identical protein binding activity. Involved in regulation of gene expression and response to virus. Located in nucleus. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.86

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.100

Z-score 1.85

OE 0.33 (0.15–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.13Z-score

OE missense 0.98 (0.87–1.10)

201 obs / 206.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.15–0.86)

0≤0.351.4

Missense OE?0.98 (0.87–1.10)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 3 / 9.0Missense obs/exp: 201 / 206.1Syn Z: -0.76

Background carrier burden — how many people carry a rare variant somewhere in CREBZF?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

543 rare PASS variants

Rare truncating (LoF)

1 in 8,800

31 rare PASS variants

Rare synonymous (reference)

1 in 250

284 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CREBZF. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 300	1 in 13,000
South Asian	~43k	1 in 160	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 130	≈ 1 in 15,000
European (Finnish)	~27k	1 in 540	1 in 3,700
Admixed American	~22k	1 in 160	1 in 2,200
African / African American	~21k	1 in 160	≈ 1 in 9,200
East Asian	~20k	1 in 220	1 in 2,300
Ashkenazi Jewish	~13k	1 in 800	none seen
Middle Eastern	~2,884	1 in 150	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓