ZFX

Chr XX-linked

zinc finger protein X-linked

Also known as: MRXS37, ZNF926

NCBI Gene: 7543 ENSG00000005889 UniProt: P17010 OMIM: 314980

ZFX encodes a transcriptional activator containing 13 zinc fingers that regulates stem cell self-renewal in hematopoietic and other tissues. Mutations cause X-linked syndromic intellectual developmental disorder 37. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.16), indicating intolerance to functional disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene on the X chromosome is structurally similar to a related gene on the Y chromosome. It encodes a member of the krueppel C2H2-type zinc-finger protein family. The full-length protein contains an acidic transcriptional activation domain (AD), a nuclear localization sequence (NLS) and a DNA binding domain (DBD) consisting of 13 C2H2-type zinc fingers. Studies in mouse embryonic and adult hematopoietic stem cells showed that this gene was required as a transcriptional regulator for self-renewal of both stem cell types, but it was dispensable for growth and differentiation of their progeny. Multiple alternatively spliced transcript variants encoding different isoforms have been identified, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismX-linkedLOEUF 0.161 OMIM phenotype

Clinical Summary— ZFX

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Gene-Disease Validity (ClinGen)

X-linked syndromic complex neurodevelopmental disorder · XLStrong

Strong evidence — appropriate for clinical testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 75 VUS of 248 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 0.998

Z-score 4.00

OE 0.00 (0.00–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.15Z-score

OE missense 0.50 (0.44–0.57)

158 obs / 315.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.16)

0≤0.351.4

Missense OE?0.50 (0.44–0.57)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 0 / 18.6Missense obs/exp: 158 / 315.2Syn Z: -0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateZFX-related neurodevelopmental disorder with hypotonia, congenital anomalies and facial dysmorphism with or without hyperparathyroidismLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.3594th %ile

GOF

0.3094th %ile

LOF

0.81top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 50% of P/LP variants are LoF · LOEUF 0.16

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

248 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic3

VUS75

Likely Benign5

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	3	0	0	7
Likely Pathogenic	1	2	0	0	3
VUS	3	71	1	0	75
Likely Benign	0	0	0	5	5
Benign	0	0	0	2	2
Total	8	76	1	7	92

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

View in ClinVar →

57 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap ZFX — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →