LRPAP1

Chr 4AR

LDL receptor related protein associated protein 1

Also known as: A2MRAP, A2RAP, HBP44, MYP23, RAP, alpha-2-MRAP

NCBI Gene: 4043 ENSG00000163956 UniProt: P30533 OMIM: 104225

This gene encodes a molecular chaperone that facilitates proper folding and localization of LDL receptor-related proteins and prevents premature ligand binding along the secretory pathway. Mutations cause autosomal recessive myopia 23, affecting vision development. The gene shows low constraint to loss-of-function variation (pLI near 0, LOEUF >1), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that interacts with the low density lipoprotein (LDL) receptor-related protein and facilitates its proper folding and localization by preventing the binding of ligands. Mutations in this gene have been identified in individuals with myopia 23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Myopia 23, autosomal recessiveMIM #615431

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Myopia 23, autosomal recessive; 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

1.17

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.17LOEUF

pLI 0.000

Z-score 1.05

OE 0.72 (0.46–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.03Z-score

OE missense 1.19 (1.08–1.32)

272 obs / 228.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.72 (0.46–1.17)

0≤0.351.4

Missense OE?1.19 (1.08–1.32)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 12 / 16.6Missense obs/exp: 272 / 228.3Syn Z: -1.07

Background carrier burden — how many people carry a rare variant somewhere in LRPAP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 50

598 rare PASS variants

Rare truncating (LoF)

1 in 1,900

91 rare PASS variants

Rare synonymous (reference)

1 in 85

274 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRPAP1. 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 67	1 in 2,000
South Asian	~43k	1 in 58	1 in 2,100
Remaining (unassigned)	~30k	1 in 50	1 in 2,700
European (Finnish)	~27k	1 in 240	≈ 1 in 8,900
Admixed American	~22k	1 in 44	1 in 2,700
African / African American	~21k	1 in 64	1 in 1,400
East Asian	~20k	1 in 90	1 in 930
Ashkenazi Jewish	~13k	1 in 860	none seen
Middle Eastern	~2,884	1 in 81	none seen

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): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓