ZNF335

Summary

ZNF335 (zinc finger protein 335, HGNC:15807) is a protein-coding gene on chromosome 20q13.12, encoding Zinc finger protein 335 (Q9H4Z2). Component or associated component of some histone methyltransferase complexes may regulate transcription through recruitment of those complexes on gene promoters. It is a selective cancer dependency (DepMap: 69.5% of cell lines).

The protein encoded by this gene enhances transcriptional activation by ligand-bound nuclear hormone receptors. However, it does this not by direct interaction with the receptor, but by direct interaction with the nuclear hormone receptor transcriptional coactivator NRC. The encoded protein may function by altering local chromatin structure.

Source: NCBI Gene 63925 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephalic primordial dwarfism due to ZNF335 deficiency (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 756 total — 13 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 30
• Cancer dependency (DepMap): dependent in 69.5% of screened cell lines
• MANE Select transcript: NM_022095

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15807
Approved symbol	ZNF335
Name	zinc finger protein 335
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	bA465L10.2, NIF-1
Ensembl gene	ENSG00000198026
Ensembl biotype	protein_coding
OMIM	610827
Entrez	63925

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000322927, ENST00000475002, ENST00000476822, ENST00000494955, ENST00000862673, ENST00000862674, ENST00000862675, ENST00000862676, ENST00000862677, ENST00000862678, ENST00000944756, ENST00000944757

RefSeq mRNA: 1 — MANE Select: NM_022095 NM_022095

CCDS: CCDS13389

Canonical transcript exons

ENST00000322927 — 28 exons

Exon	Start	End
ENSE00000845091	45949170	45949251
ENSE00000845092	45949333	45949398
ENSE00000845093	45949485	45949568
ENSE00000845094	45949800	45949877
ENSE00000845095	45949966	45950069
ENSE00000845096	45950219	45950373
ENSE00000845097	45950453	45950595
ENSE00000845098	45952147	45952521
ENSE00000845099	45952598	45952709
ENSE00000845100	45953689	45953948
ENSE00000845101	45957586	45957680
ENSE00000845102	45957835	45957928
ENSE00000845103	45959201	45959433
ENSE00000845104	45960208	45960368
ENSE00000845105	45960449	45960525
ENSE00000845106	45960616	45960732
ENSE00000845109	45963738	45963990
ENSE00000845110	45965628	45965774
ENSE00000845114	45969451	45969691
ENSE00000845115	45971210	45971460
ENSE00001225144	45963473	45963650
ENSE00001389918	45962070	45962182
ENSE00001773616	45960864	45960882
ENSE00001809926	45948660	45949080
ENSE00001824992	45972122	45972203
ENSE00003547868	45967494	45967634
ENSE00003578082	45967734	45968027
ENSE00003600563	45968285	45968362

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 91.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.7867 / max 178.4977, expressed in 1794 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187523	7.4529	1766
187521	2.1182	1039
187520	0.7510	315
209147	0.4410	253
187522	0.4074	183
187519	0.3526	174
187524	0.2636	114

Top tissues by expression

267 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	91.61	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.47	gold quality
cerebellar hemisphere	UBERON:0002245	87.99	gold quality
cerebellar cortex	UBERON:0002129	87.88	gold quality
mucosa of stomach	UBERON:0001199	87.49	gold quality
sural nerve	UBERON:0015488	87.15	gold quality
cerebellum	UBERON:0002037	87.08	gold quality
triceps brachii	UBERON:0001509	86.66	gold quality
gluteal muscle	UBERON:0002000	86.48	silver quality
right lobe of thyroid gland	UBERON:0001119	86.23	gold quality
right ovary	UBERON:0002118	85.79	gold quality
left ovary	UBERON:0002119	85.62	gold quality
spleen	UBERON:0002106	85.52	gold quality
skin of leg	UBERON:0001511	85.48	gold quality
left lobe of thyroid gland	UBERON:0001120	85.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.24	gold quality
adenohypophysis	UBERON:0002196	85.18	gold quality
pituitary gland	UBERON:0000007	85.17	gold quality
left uterine tube	UBERON:0001303	84.94	gold quality
body of uterus	UBERON:0009853	84.93	gold quality
skin of abdomen	UBERON:0001416	84.91	gold quality
body of stomach	UBERON:0001161	84.90	gold quality
tibial artery	UBERON:0007610	84.81	gold quality
popliteal artery	UBERON:0002250	84.80	gold quality
apex of heart	UBERON:0002098	84.74	gold quality
blood	UBERON:0000178	84.73	gold quality
lower esophagus mucosa	UBERON:0035834	84.60	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.36	gold quality
thyroid gland	UBERON:0002046	84.34	gold quality
right frontal lobe	UBERON:0002810	84.20	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.41

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
COPS2
CSN2
HOXA1	Activation
ISCU
REST	Unknown
S100A9
SOX9	Activation
TAC1

JASPAR motifs

Motif	Name	Family
MA2511.1	ZNF335	Other factors with up to three adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:39605320

miRNA regulators (miRDB)

33 targeting ZNF335, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-596	97.48	63.13	469
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-873-3P	96.84	66.09	786
HSA-MIR-4794	96.47	65.53	1063
HSA-MIR-664A-5P	95.84	64.93	949

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 69.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• NRC-interacting factor 1 is a novel cotransducer that interacts with and regulates the activity of the nuclear hormone receptor coactivator NRC (PMID:12215545)
• CCR4 plays a role in the regulation of certain endogenous RARalpha target genes and RCD1 and CCR4 might mediate their function through their interaction with NIF-1 (PMID:18180299)
• Study identifies and characterizes a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. (PMID:23178126)
• NIF-1 expression is associated with tumor grade in bladder cancer. (PMID:23924207)
• we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42. (PMID:25920553)
• ZNF335 gene mutation is associated with extreme microcephaly with a severely simplified gyral pattern, decreased brain size, increased extra-axial space, enlarged ventricles, absence of the corpus callosum and delayed myelination (PMID:26479514)
• In this article, we describe another family harboring ZNF335 mutations. The mutations were individually transmitted by her parents, indicating that the proband was compound heterozygous for the mutations. We speculate that invisible basal ganglia may be the key feature of ZNF335 mutations. (PMID:27540107)
• We describe, herein, 2 additional affected individuals with biallelic ZNF335 variants, 1 individual with a homozygous c.1399 T > C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A > G, p.(Glu1333Gly) variants with the latter variant predicted to affect splicing..Our findings expand the clinical spectrum of ZNF335-associated microcephaly (PMID:29652087)
• Possible effect of OAS1 and TMPRSS6 but not DPP4 and ZNF335 polymorphisms on COVID-19 severity in the Czech population. (PMID:38309700)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	znf335	ENSDARG00000076920
mus_musculus	Zfp335	ENSMUSG00000039834
rattus_norvegicus	Zfp335	ENSRNOG00000017290
drosophila_melanogaster	wek	FBGN0001990
drosophila_melanogaster	kmg	FBGN0032473
drosophila_melanogaster	CG17568	FBGN0032763
drosophila_melanogaster	CG10366	FBGN0032814
drosophila_melanogaster	CG8388	FBGN0034062
drosophila_melanogaster	CG4282	FBGN0034114
drosophila_melanogaster	CG4707	FBGN0035036
drosophila_melanogaster	CG6254	FBGN0037794
drosophila_melanogaster	CG9932	FBGN0262160

Paralogs (1): ZFP64 (ENSG00000020256)

Protein

Protein identifiers

Zinc finger protein 335 — Q9H4Z2 (reviewed: Q9H4Z2)

Alternative names: NRC-interacting factor 1

All UniProt accessions (1): Q9H4Z2

UniProt curated annotations — full annotation on UniProt →

Function. Component or associated component of some histone methyltransferase complexes may regulate transcription through recruitment of those complexes on gene promoters. Enhances ligand-dependent transcriptional activation by nuclear hormone receptors. Plays an important role in neural progenitor cell proliferation and self-renewal through the regulation of specific genes involved brain development, including REST. Also controls the expression of genes involved in somatic development and regulates, for instance, lymphoblast proliferation.

Subunit / interactions. Interacts with NCOA6; may enhance ligand-dependent transcriptional activation by nuclear hormone receptors. Interacts with CNOT6. Interacts with CNOT9; the interaction is direct. Component of a nuclear receptor-mediated transcription complex composed of at least ZNF335, CCAR2 and EMSY; the complex stimulates the transcription of nuclear receptor target genes such as SOX9 and HOXA1. Within the complex interacts with EMSY and interacts (via C-terminus) with CCAR2. Interacts with members of histone H3’Lys4’(H3K4) methyltransferase complexes ASH2L, CXXC1, KMT2A/MLL1, RBBP5, SETD1A and WDR5. Component of a histone methylation complex composed of at least ZNF335, RBBP5, ASH2L and WDR5; the complex may have histone H3-specific methyltransferase activity, however does not have specificity for ‘Lys-4’ of histone H3. Interacts with RBBP5 and WDR5. Interacts with ASHL2. Components of this complex may associate with components of the ZNF335-CCAR2-EMSY nuclear receptor-mediated transcription complex to form a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5. Within this complex also interacts with HCFC1 and MKI67.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Microcephaly 10, primary, autosomal recessive (MCPH10) [MIM:615095] A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. MCPH10 is characterized by extremely small head size and death usually by 1 year of age. Neuropathologic examination shows severe loss of neurons as well as neuronal loss of polarity and abnormal dendritic maturation. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H4Z2-1	1	yes
Q9H4Z2-2	2

RefSeq proteins (1): NP_071378* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR050688	Zinc_finger/UBP_domain	Family

Pfam: PF00096, PF13909, PF13912

UniProt features (39 total): zinc finger region 13, region of interest 6, compositionally biased region 6, sequence variant 5, modified residue 4, splice variant 2, chain 1, cross-link 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4Z2-F1	52.13	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 976, 992, 1007, 1153, 1022

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis

MSigDB gene sets: 198 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, AP2_Q3, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NEUROBLAST_PROLIFERATION, YY1_Q6, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, GOBP_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_NEURAL_PRECURSOR_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_CELL_ACTIVATION

GO Biological Process (13): in utero embryonic development (GO:0001701), positive regulation of neuroblast proliferation (GO:0002052), brain development (GO:0007420), cerebral cortex neuron differentiation (GO:0021895), epigenetic regulation of gene expression (GO:0040029), positive regulation of transcription by RNA polymerase II (GO:0045944), neuron projection morphogenesis (GO:0048812), brain morphogenesis (GO:0048854), positive regulation of lymphocyte proliferation (GO:0050671), positive regulation of neurogenesis (GO:0050769), positive regulation of cell population proliferation (GO:0008284), regulation of gene expression (GO:0010468), regulation of neurogenesis (GO:0050767)

GO Molecular Function (7): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), zinc ion binding (GO:0008270), histone methyltransferase binding (GO:1990226), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), histone methyltransferase complex (GO:0035097)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Activation of HOX genes during differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neurogenesis	2
chordate embryonic development	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
central nervous system development	1
animal organ development	1
head development	1
forebrain neuron differentiation	1
chromatin remodeling	1
regulation of gene expression	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
brain development	1
animal organ morphogenesis	1
positive regulation of mononuclear cell proliferation	1
lymphocyte proliferation	1
regulation of lymphocyte proliferation	1
positive regulation of lymphocyte activation	1
positive regulation of cell development	1
regulation of neurogenesis	1
positive regulation of nervous system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
regulation of nervous system development	1
regulation of cell development	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transition metal ion binding	1
enzyme binding	1
nucleic acid binding	1

Protein interactions and networks

STRING

1096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNF335	YIPF6	Q96EC8	772
ZNF335	SASS6	Q6UVJ0	692
ZNF335	WDR62	O43379	691
ZNF335	ANKLE2	Q86XL3	683
ZNF335	MFSD2A	Q8NA29	681
ZNF335	CEP135	Q66GS9	664
ZNF335	MCPH1	Q8NEM0	651
ZNF335	CPAP	Q9HC77	643
ZNF335	STIL	Q15468	633
ZNF335	CEP152	O94986	621
ZNF335	PHC1	P78364	610
ZNF335	ASPM	Q8IZT6	607
ZNF335	CDK5RAP2	Q96SN8	591
ZNF335	PCIF1	Q9H4Z3	584
ZNF335	KNL1	Q8NG31	575

IntAct

21 interactions, top by confidence:

A	B	Type	Score
ASH2L	RBBP5	psi-mi:“MI:0914”(association)	0.980
ASH2L	WDR5	psi-mi:“MI:0914”(association)	0.950
CCAR2	ZNF335	psi-mi:“MI:0915”(physical association)	0.620
ZNF335	EMSY	psi-mi:“MI:0914”(association)	0.580
RPSA	RPS17	psi-mi:“MI:0914”(association)	0.530
ZNF335	MKI67	psi-mi:“MI:0914”(association)	0.460
ZNF335	CDK6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CDK4	ZNF335	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
HSPB2	ZNF335	psi-mi:“MI:0915”(physical association)	0.370
ZNF335	TUBB	psi-mi:“MI:0914”(association)	0.350
CCAR2	EMSY	psi-mi:“MI:0914”(association)	0.350
EMSY	RBBP5	psi-mi:“MI:0914”(association)	0.350
	ARID1A	psi-mi:“MI:0914”(association)	0.350
rl3_rl3l_human	NKRF	psi-mi:“MI:0914”(association)	0.350
NOTCH2	ZNF320	psi-mi:“MI:0914”(association)	0.350
GLI4	ZNF316	psi-mi:“MI:0914”(association)	0.350
SRSF5	FBLL1	psi-mi:“MI:0914”(association)	0.350
KRR1	PES1	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
NPM1	SBNO1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (39): Rqcd1 (Two-hybrid), ZNF335 (Reconstituted Complex), ZNF335 (Affinity Capture-Western), ZNF335 (Affinity Capture-Western), ZNF335 (Affinity Capture-MS), ZNF335 (Two-hybrid), ZNF335 (Affinity Capture-MS), ZNF335 (Affinity Capture-MS), ZNF335 (Affinity Capture-MS), ZNF335 (Reconstituted Complex), ZNF335 (Two-hybrid), ZNF335 (Affinity Capture-MS), ZNF335 (Affinity Capture-MS), ZNF335 (Affinity Capture-MS), ZNF335 (Affinity Capture-MS)

ESM2 similar proteins: A2A5E6, A5PK23, A6NKF2, A6PWV5, B0K011, E9Q6W4, O02786, O95402, P09086, P13297, P55198, Q00196, Q08DS3, Q0VDQ9, Q29013, Q2NKI2, Q2VL80, Q2VL82, Q2VL83, Q2VL85, Q2VL86, Q569K4, Q5XI28, Q62255, Q66K41, Q6AXX3, Q6PBT9, Q86V15, Q8BXJ8, Q8IVH2, Q8K4J6, Q8TAX0, Q8VD12, Q8VDL9, Q8WUU4, Q92766, Q969V6, Q96PM9, Q9BXA9, Q9BZE0

Diamond homologs: A2A5K6, G3V893, O60315, P28166, P36197, Q01789, Q02033, Q60542, Q62947, Q64318, Q9H4Z2, Q9R0G7, A0A5E4M3Q4, A0JC51, A2ANX9, B0X9H6, B0XS89, B1WBU4, F1QQA8, G5EBU4, O57311, O77459, P10925, P15822, P17012, P22227, P25490, P31509, P37275, P39956, P56270, P56670, P56671, P60319, Q00899, Q01611, Q01800, Q02026, Q02027, Q03172

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cellular responses to stress	6	13.0×	2e-04
Cellular responses to stimuli	6	11.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

756 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	11
Uncertain significance	368
Likely benign	233
Benign	57

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1686312	NM_022095.4(ZNF335):c.3014_3015insG (p.Ser1007fs)	Pathogenic
1973912	NM_022095.4(ZNF335):c.3209C>G (p.Ser1070Ter)	Pathogenic
2073392	NM_022095.4(ZNF335):c.652C>T (p.Gln218Ter)	Pathogenic
225017	NM_022095.4(ZNF335):c.3332G>T (p.Arg1111Leu)	Pathogenic
2761650	NM_022095.4(ZNF335):c.1797dup (p.Lys600Ter)	Pathogenic
2964823	NM_022095.4(ZNF335):c.2663del (p.Pro888fs)	Pathogenic
3475354	NM_022095.4(ZNF335):c.3523_3524insGGCCCTG (p.Glu1175delinsGlyProTer)	Pathogenic
375392	NM_022095.4(ZNF335):c.3787G>T (p.Glu1263Ter)	Pathogenic
40116	NM_022095.4(ZNF335):c.3332G>A (p.Arg1111His)	Pathogenic
4685505	NM_022095.4(ZNF335):c.3576_3577del (p.Gln1192fs)	Pathogenic
4819381	NM_022095.4(ZNF335):c.2558del (p.Gly853fs)	Pathogenic
521497	NM_022095.4(ZNF335):c.757dup (p.Arg253fs)	Pathogenic
619006	NM_022095.4(ZNF335):c.1399T>C (p.Cys467Arg)	Pathogenic
2075061	NM_022095.4(ZNF335):c.2443-2A>T	Likely pathogenic
212646	NM_022095.4(ZNF335):c.2515_2518dup (p.Thr840fs)	Likely pathogenic
3255579	NM_022095.4(ZNF335):c.1460A>G (p.His487Arg)	Likely pathogenic
3357841	NM_022095.4(ZNF335):c.1063del (p.Arg355fs)	Likely pathogenic
3674476	NM_022095.4(ZNF335):c.3488-1G>A	Likely pathogenic
3780812	NM_022095.4(ZNF335):c.315del (p.Val107fs)	Likely pathogenic
3780813	NM_022095.4(ZNF335):c.3487+1G>C	Likely pathogenic
3911868	NM_022095.4(ZNF335):c.3298G>T (p.Glu1100Ter)	Likely pathogenic
445926	NM_022095.4(ZNF335):c.1356-1G>A	Likely pathogenic
619007	NM_022095.4(ZNF335):c.1505A>G (p.Tyr502Cys)	Likely pathogenic
817743	NM_022095.4(ZNF335):c.1887_1890del (p.Cys630fs)	Likely pathogenic

SpliceAI

4262 predictions. Top by Δscore:

Variant	Effect	Δscore
20:45949078:CTG:C	acceptor_gain	1.0000
20:45949085:C:CT	acceptor_gain	1.0000
20:45949086:A:T	acceptor_gain	1.0000
20:45949165:CATAC:C	donor_loss	1.0000
20:45949167:TACC:T	donor_loss	1.0000
20:45949169:C:CA	donor_loss	1.0000
20:45949251:TC:T	acceptor_loss	1.0000
20:45949252:C:CC	acceptor_gain	1.0000
20:45949252:CTGG:C	acceptor_loss	1.0000
20:45949327:CCCTA:C	donor_loss	1.0000
20:45949328:CCTA:C	donor_loss	1.0000
20:45949329:CTACC:C	donor_loss	1.0000
20:45949330:TA:T	donor_loss	1.0000
20:45949331:ACC:A	donor_loss	1.0000
20:45949332:CCTGG:C	donor_loss	1.0000
20:45949340:T:TA	donor_gain	1.0000
20:45949396:TACCT:T	acceptor_loss	1.0000
20:45949398:CCTGC:C	acceptor_loss	1.0000
20:45949399:C:A	acceptor_loss	1.0000
20:45949399:C:CC	acceptor_gain	1.0000
20:45949402:C:CT	acceptor_gain	1.0000
20:45949480:CCTA:C	donor_loss	1.0000
20:45949481:CTA:C	donor_loss	1.0000
20:45949482:TAC:T	donor_loss	1.0000
20:45949483:A:C	donor_loss	1.0000
20:45949484:CCTG:C	donor_loss	1.0000
20:45949794:GCTCA:G	donor_loss	1.0000
20:45949795:CTCAC:C	donor_loss	1.0000
20:45949796:TCACC:T	donor_loss	1.0000
20:45949797:CACCT:C	donor_loss	1.0000

AlphaMissense

8752 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:45950370:G:C	F1112L	1.000
20:45950370:G:T	F1112L	1.000
20:45950372:A:G	F1112L	1.000
20:45960277:A:G	C651R	1.000
20:45960361:A:G	C623R	1.000
20:45960472:G:C	H612Q	1.000
20:45960472:G:T	H612Q	1.000
20:45960479:A:G	L610P	1.000
20:45960482:A:G	L609P	1.000
20:45960484:G:C	H608Q	1.000
20:45960484:G:T	H608Q	1.000
20:45960486:G:C	H608D	1.000
20:45960494:A:G	F605S	1.000
20:45960511:A:C	F599L	1.000
20:45960511:A:T	F599L	1.000
20:45960512:A:C	F599C	1.000
20:45960512:A:G	F599S	1.000
20:45960513:A:G	F599L	1.000
20:45960525:A:G	C595R	1.000
20:45960622:A:C	C592W	1.000
20:45960623:C:A	C592F	1.000
20:45960623:C:G	C592S	1.000
20:45960623:C:T	C592Y	1.000
20:45960624:A:G	C592R	1.000
20:45960624:A:T	C592S	1.000
20:45960699:A:G	C567R	1.000
20:45960706:G:C	C564W	1.000
20:45960708:A:G	C564R	1.000
20:45962120:A:C	S532R	1.000
20:45962120:A:T	S532R	1.000

dbSNP variants (sampled 300 via entrez): RS1000064395 (20:45972854 A>C,G), RS1000205028 (20:45960896 G>A), RS1000472642 (20:45950555 C>T), RS1000589088 (20:45956952 C>A), RS1000654279 (20:45957989 C>A,T), RS1000976836 (20:45970611 T>A,C), RS1000992576 (20:45967730 G>A), RS1001050293 (20:45970257 C>T), RS1001092626 (20:45962363 G>A), RS1001146739 (20:45962518 G>A), RS1001221357 (20:45973622 G>A), RS1001280995 (20:45964631 C>G), RS1001343379 (20:45967532 T>C), RS1001441681 (20:45956563 G>A), RS1001514931 (20:45950118 A>G)

Disease associations

OMIM: gene MIM:610827 | disease phenotypes: MIM:615095, MIM:251200, MIM:209850, MIM:609924

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephalic primordial dwarfism due to ZNF335 deficiency	Strong	Autosomal recessive

Mondo (4): microcephalic primordial dwarfism due to ZNF335 deficiency (MONDO:0014043), autosomal recessive primary microcephaly (MONDO:0016660), autism (MONDO:0005260), aminoacylase 1 deficiency (MONDO:0012368)

Orphanet (3): Microcephalic primordial dwarfism due to ZNF335 deficiency (Orphanet:329228), Autosomal recessive primary microcephaly (Orphanet:2512), Aminoacylase 1 deficiency (Orphanet:137754)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000426	Prominent nasal bridge
HP:0000453	Choanal atresia
HP:0000518	Cataract
HP:0001257	Spasticity
HP:0001272	Cerebellar atrophy
HP:0001274	Agenesis of corpus callosum
HP:0001276	Hypertonia
HP:0001317	Abnormal cerebellum morphology
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0002059	Cerebral atrophy
HP:0002060	Abnormal cerebral morphology
HP:0002119	Ventriculomegaly
HP:0002171	Gliosis
HP:0002188	Delayed CNS myelination
HP:0002472	Small cerebral cortex
HP:0002538	Abnormal cerebral cortex morphology
HP:0002804	Arthrogryposis multiplex congenita
HP:0003577	Congenital onset
HP:0009879	Simplified gyral pattern
HP:0011344	Severe global developmental delay
HP:0011451	Primary microcephaly
HP:0012444	Brain atrophy
HP:0012757	Abnormal neuron morphology
HP:0034295	Reduced cerebral white matter volume
HP:0100307	Cerebellar hemisphere hypoplasia

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003681_21	C-reactive protein levels or triglyceride levels (pleiotropy)	2.000000e-24
GCST003877_9	Abdominal aortic aneurysm	2.000000e-17
GCST005195_86	Coronary artery disease	4.000000e-09
GCST005196_246	Coronary artery disease	3.000000e-09
GCST005316_239	Intelligence (MTAG)	3.000000e-08
GCST006269_746	General cognitive ability	1.000000e-08
GCST008489_14	Celiac disease	5.000000e-08
GCST010866_167	Coronary artery disease	7.000000e-11
GCST011365_114	Myocardial infarction	6.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0004530	triglyceride measurement
EFO:0004337	intelligence

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
C538246	Aminoacylase 1 deficiency (supp.)
C579935	Autosomal Recessive Primary Microcephaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3827066	ZNF335		0.00	0

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
trichostatin A	affects expression	1
cobaltous chloride	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
1-hydroxypyrene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
Bortezomib	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lead	increases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Urethane	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_HD21	HEK293 eGFP-ZNF335	Transformed cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms