P4HTM

Chr 3

prolyl 4-hydroxylase, transmembrane

Also known as: EGLN4, HIDEA, HIFPH4, P4H-TM, PH-4, PH4, PHD4

NCBI Gene: 54681ENSG00000178467UniProt: Q9NXG6

The product of this gene belongs to the family of prolyl 4-hydroxylases. This protein is a prolyl hydroxylase that may be involved in the degradation of hypoxia-inducible transcription factors under normoxia. It plays a role in adaptation to hypoxia and may be related to cellular oxygen sensing. Alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtHypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities
135
ClinVar variants
26
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— P4HTM
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 93 VUS of 135 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.00LOEUF
pLI 0.000
Z-score 1.54
OE 0.67 (0.46–1.00)
Tolerant

Highly tolerant — LoF variants common in population

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.
1.54Z-score
OE missense 0.76 (0.69–0.84)
253 obs / 332.1 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.0.67 (0.46–1.00)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.69–0.84)
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.0.97
0≤1.21.6
LoF obs/exp: 17 / 25.4Missense obs/exp: 253 / 332.1Syn Z: 0.23

ClinVar Variant Classifications

135 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic9
VUS93
Likely Benign13
Benign1
Conflicting2
17
Pathogenic
9
Likely Pathogenic
93
VUS
13
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
14
0
17
Likely Pathogenic
3
4
2
0
9
VUS
3
84
6
0
93
Likely Benign
0
4
1
8
13
Benign
0
0
1
0
1
Conflicting
—2
Total893248135

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

View in ClinVar →

Protein Context — Lollipop Plot

P4HTM · protein map & ClinVar variants

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

Gene2Phenotype Curations

P4HTM-related hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein.
Kraatari-Tiri M et al.·Clin Genet
2022Review
Further delineation of HIDEA syndrome.
Maddirevula S et al.·Am J Med Genet A
2020Case report
Rare variant analyses across multiethnic cohorts identify novel genes for refractive error.
Musolf AM et al.·Commun Biol
2023Cohort
Biallelic Mutations in P4HTM Cause Syndromic Obesity.
Saeed S et al.·Diabetes
2023
A pathogenic P4HTM gene variant in two brothers with autism spectrum disorder.
Gülcü Üstün NS·Psychiatr Genet
2024Case report
Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome).
Rahikkala E et al.·Genet Med
2019
Novel compound heterozygous P4HTM variants in a girl with developmental and epileptic encephalopathy: First case report of P4HTM variant-associated epileptic encephalopathy.
Alomarı O et al.·Seizure
2025Case report
Dual prognostic role of 2-oxoglutarate-dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance.
Chang WH et al.·Cancer Commun (Lond)
2019
Clinical characterization, genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome.
Kaasinen E et al.·Eur J Med Genet
2014Case report
HIDEA syndrome: A rare cause of congenital hypoventilation in a premature infant.
Lim AM et al.·Pediatr Pulmonol
2022Case report
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
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools