P4HTM

Chr 3AR

prolyl 4-hydroxylase, transmembrane

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

NCBI Gene: 54681 ENSG00000178467 UniProt: Q9NXG6 OMIM: 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.

OMIM ResearchSummary from OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.001 OMIM phenotype

Clinical Summary— P4HTM

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 91 VUS of 126 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 →

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 OE?0.67 (0.46–1.00)

0≤0.351.4

Missense OE?0.76 (0.69–0.84)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 17 / 25.4Missense obs/exp: 253 / 332.1Syn Z: 0.23

ClinVar Variant Classifications

126 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic7

VUS91

Likely Benign13

Benign1

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	1	0	0	6
Likely Pathogenic	3	4	0	0	7
VUS	3	85	3	0	91
Likely Benign	0	4	1	8	13
Benign	0	0	1	0	1
Conflicting	—				2
Total	11	94	5	8	120

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap P4HTM — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →