PHEX

Chr XXLD

phosphate regulating endopeptidase X-linked

Also known as: HPDR, HPDR1, HYP, HYP1, LXHR, PEX, XLH

NCBI Gene: 5251 ENSG00000102174 UniProt: P78562

The protein encoded by this gene is a transmembrane endopeptidase that belongs to the type II integral membrane zinc-dependent endopeptidase family. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption. Mutations in this gene cause X-linked hypophosphatemic rickets. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

Primary Disease Associations & Inheritance

Hypophosphatemic rickets, X-linked dominantMIM #307800

XLD

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

1.7

Missense Z

0.14

LOEUF· LoF intolerant

Clinical Summary— PHEX

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Gene-Disease Validity (ClinGen)

X-linked dominant hypophosphatemic rickets · 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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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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.

0.14LOEUF

pLI 1.000

Z-score 5.18

OE 0.03 (0.01–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.

1.71Z-score

OE missense 0.72 (0.64–0.81)

211 obs / 293.4 exp

Tolerant

Mild missense constraint

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.0.03 (0.01–0.14)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.64–0.81)

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.1.04

0≤1.21.6

LoF obs/exp: 1 / 33.2Missense obs/exp: 211 / 293.4Syn Z: -0.31

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PHEX · protein map & ClinVar variants

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

Gene2Phenotype Curations

PHEX-related hypophosphatemic rickets

definitive

Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure

Dev. DisordersSkeletal

G2P ↗

splice region variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletionsynonymous variantintron variantinframe insertionwhole partial gene deletionwhole partial gene duplication

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