ZMYND8

Chr 20

zinc finger MYND-type containing 8

Also known as: PRKCBP1, PRO2893, RACK7

NCBI Gene: 23613 ENSG00000101040 UniProt: Q9ULU4 OMIM: 615713

The encoded protein is a transcriptional regulator containing a bromodomain and two zinc fingers that binds to activated protein kinase C beta I. Loss-of-function mutations in ZMYND8 cause autosomal dominant neurodevelopmental disorder, as evidenced by the extremely high pLI score (>0.99) and very low LOEUF score (0.131) indicating strong intolerance to loss-of-function variants. The pathogenic mechanism involves haploinsufficiency of this nuclear transcriptional regulator.

OMIM ResearchSummary from RefSeq, UniProt, Mechanism

The protein encoded by this gene is a receptor for activated C-kinase (RACK) protein. The encoded protein has been shown to bind in vitro to activated protein kinase C beta I. In addition, this protein is a cutaneous T-cell lymphoma-associated antigen. Finally, the protein contains a bromodomain and two zinc fingers, and is thought to be a transcriptional regulator. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · syndromic complex neurodevelopmental disorder · AD · ClinGen 2026

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.13

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 6.77

OE 0.05 (0.02–0.13)

Highly constrained

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

Missense Constraint?

4.04Z-score

OE missense 0.57 (0.53–0.62)

399 obs / 699.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.13)

0≤0.351.4

Missense OE?0.57 (0.53–0.62)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 59.2Missense obs/exp: 399 / 699.6Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in ZMYND8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 67

1,243 rare PASS variants

Rare truncating (LoF)

1 in 1,300

101 rare PASS variants

Rare synonymous (reference)

1 in 77

624 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZMYND8. 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 78	1 in 2,700
South Asian	~43k	1 in 52	1 in 2,300
Remaining (unassigned)	~30k	1 in 50	1 in 1,200
European (Finnish)	~27k	1 in 180	1 in 1,900
Admixed American	~22k	1 in 54	1 in 1,800
African / African American	~21k	1 in 52	1 in 410
East Asian	~20k	1 in 71	1 in 2,400
Ashkenazi Jewish	~13k	1 in 240	1 in 1,500
Middle Eastern	~2,884	1 in 63	≈ 1 in 1,400

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 23 coding exons well covered in gnomAD exomes and genomes.? see exons ↓