PHF6

Chr XXLR

PHD finger protein 6

Also known as: BFLS, BORJ, CENP-31

NCBI Gene: 84295ENSG00000156531UniProt: Q8IWS0OMIM: 300414

The protein contains two PHD-type zinc finger domains and localizes to the nucleolus where it functions in transcriptional regulation. Mutations cause Borjeson-Forssman-Lehmann syndrome, an X-linked recessive disorder characterized by cognitive disability, epilepsy, hypogonadism, hypometabolism, obesity, facial swelling, narrow palpebral fissures, and large ears. The pathogenic mechanism involves loss of function of this highly constrained protein.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismXLRLOEUF 0.171 OMIM phenotype
Clinical Summary— PHF6
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Gene-Disease Validity (ClinGen)
Borjeson-Forssman-Lehmann syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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
130 unique Pathogenic / Likely Pathogenic· 98 VUS of 334 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — PHF6
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.17LOEUF
pLI 0.998
Z-score 3.93
OE 0.00 (0.00–0.17)
Highly constrained

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

Missense Constraint
2.28Z-score
OE missense 0.44 (0.35–0.55)
57 obs / 130.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.17)
0≤0.351.4
Missense OE0.44 (0.35–0.55)
0≤0.61.4
Synonymous OE1.10
0≤1.21.6
LoF obs/exp: 0 / 18.0Missense obs/exp: 57 / 130.4Syn Z: -0.50
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitivePHF6-related Boerjeson-Forssman-Lehmann syndromeLOFmonoallelic_X_heterozygous
DN
0.17100th %ile
GOF
0.2098th %ile
LOF
0.79top 5%

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

LOFprediction above median · 20% of P/LP variants are LoF · LOEUF 0.17

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

334 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic110
Likely Pathogenic20
VUS98
Likely Benign72
Benign20
Conflicting5
110
Pathogenic
20
Likely Pathogenic
98
VUS
72
Likely Benign
20
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
11
80
0
110
Likely Pathogenic
7
11
2
0
20
VUS
2
80
14
2
98
Likely Benign
0
5
36
31
72
Benign
0
1
15
4
20
Conflicting
—5
Total2810814737325

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

View in ClinVar →

Protein Context — Lollipop Plot

PHF6 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Computational Insights Into the Inhibition Mechanism of Proanthocyanidin B2 on Tau Hexapeptide (PHF6) Oligomer
Li Q et al.·Front Chem
2021Functional
PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia
Tsai HI et al.·Acta Pharm Sin B
2022
Exploring the Aggregation Propensity of PHF6 Peptide Segments of the Tau Protein Using Ion Mobility Mass Spectrometry Techniques
Stroganova I et al.·Anal Chem
2024
Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study
Zou Y et al.·Front Mol Biosci
2021
Deciphering the Inhibitory Mechanism of Naphthoquinone-Dopamine on the Aggregation of Tau Core Fragments PHF6* and PHF6.
Zou Y et al.·ACS Chem Neurosci
2023Functional
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients