P3H2

Chr 3AR

prolyl 3-hydroxylase 2

Also known as: LEPREL1, MCVD, MLAT4

NCBI Gene: 55214 ENSG00000090530 UniProt: Q8IVL5 OMIM: 610341

This gene encodes a member of the prolyl 3-hydroxylase subfamily of 2-oxo-glutarate-dependent dioxygenases. These enzymes play a critical role in collagen chain assembly, stability and cross-linking by catalyzing post-translational 3-hydroxylation of proline residues. Mutations in this gene are associated with nonsyndromic severe myopia with cataract and vitreoretinal degeneration, and downregulation of this gene may play a role in breast cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

OMIM Research

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Myopia, high, with cataract and vitreoretinal degenerationMIM #614292

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Myopia, high, with cataract and vitreoretinal degeneration; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.16

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.16LOEUF

pLI 0.000

Z-score 0.77

OE 0.87 (0.66–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.24Z-score

OE missense 1.03 (0.95–1.13)

389 obs / 376.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.87 (0.66–1.16)

0≤0.351.4

Missense OE?1.03 (0.95–1.13)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 34 / 39.2Missense obs/exp: 389 / 376.1Syn Z: -0.64

Background carrier burden — how many people carry a rare variant somewhere in P3H2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 52

1,079 rare PASS variants

Rare truncating (LoF)

1 in 620

178 rare PASS variants

Rare synonymous (reference)

1 in 110

393 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for P3H2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 72	1 in 600
South Asian	~43k	1 in 50	1 in 450
Remaining (unassigned)	~30k	1 in 39	1 in 970
European (Finnish)	~27k	1 in 220	1 in 890
Admixed American	~22k	1 in 53	1 in 900
African / African American	~21k	1 in 55	1 in 910
East Asian	~20k	1 in 53	1 in 770
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 2,700
Middle Eastern	~2,884	1 in 62	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 15 coding exons well covered in gnomAD exomes; exon 13 marginal. Genomes: all 15.? see exons ↓