ZNF646

Chr 16

zinc finger protein 646

NCBI Gene: 9726 ENSG00000167395 UniProt: O15015 OMIM: 619299

ZNF646 encodes a zinc finger transcription factor that binds DNA and regulates gene transcription in the nucleus. Mutations cause autosomal recessive intellectual disability with developmental delay. The gene is highly intolerant to loss-of-function variants (pLI nearly 1.0), indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of DNA-templated transcription. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 0.52

Clinical Summary— ZNF646

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

310 VUS of 343 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 4.37

OE 0.36 (0.25–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.64Z-score

OE missense 0.95 (0.90–1.00)

1080 obs / 1140.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.25–0.52)

0≤0.351.4

Missense OE?0.95 (0.90–1.00)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 19 / 53.5Missense obs/exp: 1080 / 1140.6Syn Z: -0.68

ClinVar Variant Classifications

343 submitted variants in ClinVar

ClinVar

Classification Summary

VUS310

Likely Benign24

310

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	310	0	310
Likely Benign	21	3	24
Benign	0	0	0
Total	331	3	334

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap ZNF646 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →