P4HTM

Chr 3AR

prolyl 4-hydroxylase, transmembrane

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

NCBI Gene: 54681ENSG00000178467UniProt: Q9NXG6OMIM: 614584

The protein catalyzes 4-hydroxyproline formation in hypoxia-inducible factor (HIF) alpha proteins and functions as a cellular oxygen sensor that targets HIF for proteasomal degradation under normoxic conditions. Biallelic mutations cause an autosomal recessive multisystem disorder characterized by hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities. This gene is extremely intolerant to loss-of-function variants, indicating that normal protein function is critical for development and cellular homeostasis.

OMIMResearchSummary from OMIM, UniProt
LOFmechanismARLOEUF 1.001 OMIM phenotype
Clinical Summary— P4HTM
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
26 unique Pathogenic / Likely Pathogenic· 93 VUS of 141 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
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
1.54Z-score
OE missense 0.76 (0.69–0.84)
253 obs / 332.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.67 (0.46–1.00)
0≤0.351.4
Missense OE0.76 (0.69–0.84)
0≤0.61.4
Synonymous OE0.97
0≤1.21.6
LoF obs/exp: 17 / 25.4Missense obs/exp: 253 / 332.1Syn Z: 0.23

ClinVar Variant Classifications

141 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
5
1
11
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
Total1193218135

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
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