ZIC4

Chr 3

Zic family zinc finger 4

NCBI Gene: 84107 ENSG00000174963 UniProt: Q8N9L1 OMIM: 608948

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development, and have been associated with X-linked visceral heterotaxy and holoprosencephaly type 5. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 1, a related family member on chromosome 3. Heterozygous deletion of these linked genes is involved in Dandy-Walker malformation, which is a congenital cerebellar malformation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Dec 2009]

OMIM Research

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.87

Clinical Summary— ZIC4

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

106 VUS of 166 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 1.95

OE 0.48 (0.28–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.11Z-score

OE missense 1.02 (0.92–1.14)

230 obs / 225.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.48 (0.28–0.87)

0≤0.351.4

Missense OE?1.02 (0.92–1.14)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 8 / 16.5Missense obs/exp: 230 / 225.2Syn Z: -1.71

This gene — mechanism propensity

0.74top 25%

GOF

0.4184th %ile

LOF

0.58top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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.

ClinVar Variant Classifications

166 submitted variants in ClinVar

ClinVar

Classification Summary

VUS106

Likely Benign45

Benign9

Conflicting1

106

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	3	102	1	0	106
Likely Benign	0	4	13	28	45
Benign	0	4	2	3	9
Conflicting	—				1
Total	3	110	16	31	161

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ZIC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →