ZNF335

Chr 20AR

zinc finger protein 335

Also known as: MCPH10, NIF-1, NIF1, NIF2

NCBI Gene: 63925 ENSG00000198026 UniProt: Q9H4Z2 OMIM: 610827

The protein is a component of histone methyltransferase complexes that enhances ligand-dependent transcriptional activation by nuclear hormone receptors and plays an important role in neural progenitor cell proliferation and self-renewal through regulation of genes involved in brain development. Mutations cause microcephaly 10, primary, autosomal recessive, which presents with congenital microcephaly. The gene is highly constrained against loss-of-function variation (LOEUF 0.501), reflecting its critical role in neurodevelopment.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microcephaly 10, primary, autosomal recessiveMIM #615095

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Microcephaly 10, primary, autosomal recessive; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.50

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.000

Z-score 4.83

OE 0.35 (0.25–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.55Z-score

OE missense 0.95 (0.89–1.00)

795 obs / 839.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.25–0.50)

0≤0.351.4

Missense OE?0.95 (0.89–1.00)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 23 / 65.0Missense obs/exp: 795 / 839.8Syn Z: -0.63

Background carrier burden — how many people carry a rare variant somewhere in ZNF335?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 28

1,969 rare PASS variants

Rare truncating (LoF)

1 in 500

224 rare PASS variants

Rare synonymous (reference)

1 in 62

821 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZNF335. 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 40	1 in 470
South Asian	~43k	1 in 30	1 in 930
Remaining (unassigned)	~30k	1 in 25	1 in 560
European (Finnish)	~27k	1 in 110	1 in 920
Admixed American	~22k	1 in 26	1 in 350
African / African American	~21k	1 in 29	1 in 1,100
East Asian	~20k	1 in 37	1 in 430
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 27	≈ 1 in 580

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): 26 of 27 coding exons well covered in gnomAD exomes; exon 15 marginal. Genomes: all 27.? see exons ↓