ZDHHC8

Chr 22

zDHHC palmitoyltransferase 8

Also known as: DHHC8, ZDHHCL1, ZNF378

NCBI Gene: 29801 ENSG00000099904 UniProt: Q9ULC8 OMIM: 608784

The protein functions as a palmitoyltransferase that adds palmitate to various protein substrates, including ABCA1 (regulating cholesterol transport) and potentially the D2 dopamine receptor, thereby controlling their plasma membrane localization and function. Mutations in this gene may be associated with susceptibility to schizophrenia, though definitive pediatric neurological phenotypes are not well-established. The gene is highly constrained against loss-of-function variants (pLI 0.85, LOEUF 0.37), suggesting that complete loss of function is likely deleterious.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a four transmembrane protein that is a member of the zinc finger DHHC domain-containing protein family. The encoded protein may function as a palmitoyltransferase. Defects in this gene may be associated with a susceptibility to schizophrenia. Alternate splicing of this gene results in multiple transcript variants. A pseudogene of this gene is found on chromosome 22.[provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.37

Clinical Summary— ZDHHC8

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.

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ClinVar Variants

151 VUS of 173 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.853

Z-score 4.06

OE 0.18 (0.09–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.85Z-score

OE missense 0.77 (0.71–0.84)

403 obs / 522.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.09–0.37)

0≤0.351.4

Missense OE?0.77 (0.71–0.84)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 5 / 28.3Missense obs/exp: 403 / 522.1Syn Z: -1.53

This gene — mechanism propensity

0.5576th %ile

GOF

0.6542th %ile

LOF

0.68top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.37

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

173 submitted variants in ClinVar

ClinVar

Classification Summary

VUS151

Likely Benign8

151

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	151	0	151
Likely Benign	6	2	8
Benign	0	0	0
Total	157	2	159

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

View in ClinVar →

388 pathogenic / likely-pathogenic (of 403) ClinVar copy-number / structural variants overlap ZDHHC8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →