PHF8

Chr XXLR

PHD finger protein 8

Also known as: JHDM1F, KDM7B, MRXSSD, ZNF422

NCBI Gene: 23133ENSG00000172943UniProt: Q9UPP1

The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD) and over-expression of this gene is associated with several forms of cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Siderius typeMIM #300263
XLR
326
ClinVar variants
84
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— PHF8
🧬
Gene-Disease Validity (ClinGen)
syndromic X-linked intellectual disability Siderius type · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
84 Pathogenic / Likely Pathogenic· 166 VUS of 326 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.26LOEUF
pLI 0.998
Z-score 5.13
OE 0.12 (0.06–0.26)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.98Z-score
OE missense 0.46 (0.41–0.52)
199 obs / 431.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.06–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.41–0.52)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 5 / 40.0Missense obs/exp: 199 / 431.4Syn Z: 0.43

ClinVar Variant Classifications

326 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic15
VUS166
Likely Benign64
Benign7
Conflicting5
69
Pathogenic
15
Likely Pathogenic
166
VUS
64
Likely Benign
7
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
1
59
0
69
Likely Pathogenic
6
1
8
0
15
VUS
5
139
19
3
166
Likely Benign
0
13
7
44
64
Benign
0
0
3
4
7
Conflicting
—5
Total201549651326

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

View in ClinVar →

Protein Context — Lollipop Plot

PHF8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PHF8-related syndromic intellectual developmental disorder, Siderius type

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked syndromic, Siderius type

MIM #300263

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Homocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease.
Jakubowski H et al.·Int J Mol Sci
2025Review
Disrupting PHF8-TOPBP1 connection elicits a breast tumor-specific vulnerability to chemotherapeutics.
Ma S et al.·Cancer Lett
2022
Epigenetic control over the cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia.
Felipe Fumero E et al.·Blood
2024
HER3 promotes triple-negative breast cancer progression by upregulating PHF8 via miR-34b-5p-dependent mechanism.
Lyu H et al.·Cell Death Dis
2025Functional
PHF8 Plays an Oncogene Function in Hepatocellular Carcinoma Formation.
Ye H et al.·Oncol Res
2019
Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders.
Schrauwen I et al.·Sci Rep
2024
Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer.
Tseng LL et al.·Proc Natl Acad Sci U S A
2020
A non-canonical role of ELN protects from cellular senescence by limiting iron-dependent regulation of gene expression.
Czarnecka-Herok J et al.·Redox Biol
2024
The histone demethylase PHF8 promotes adult acute lymphoblastic leukemia through interaction with the MEK/ERK signaling pathway.
Fu Y et al.·Biochem Biophys Res Commun
2018
c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer.
Maina PK et al.·Oncotarget
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools