LRP12

Chr 8AD

LDL receptor related protein 12

Also known as: ALS28, MIG13A, ST7

NCBI Gene: 29967 ENSG00000147650 UniProt: Q9Y561 OMIM: 618299

This gene encodes a transmembrane receptor protein involved in internalization of lipophilic molecules and signal transduction. Mutations cause amyotrophic lateral sclerosis 28 and oculopharyngodistal myopathy 1 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.998, LOEUF 0.256), indicating intolerance to protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the low-density lipoprotein receptor related protein family. The product of this gene is a transmembrane protein that is differentially expressed in many cancer cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 28MIM #620452

Oculopharyngodistal myopathy 1MIM #164310

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · oculopharyngodistal myopathy 1 · AD · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.998

Z-score 4.92

OE 0.11 (0.05–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.30Z-score

OE missense 0.83 (0.77–0.90)

397 obs / 477.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.05–0.26)

0≤0.351.4

Missense OE?0.83 (0.77–0.90)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 4 / 35.8Missense obs/exp: 397 / 477.2Syn Z: -0.90

Background carrier burden — how many people carry a rare variant somewhere in LRP12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 88

951 rare PASS variants

Rare truncating (LoF)

1 in 3,500

77 rare PASS variants

Rare synonymous (reference)

1 in 170

382 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRP12. 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 96	1 in 3,600
South Asian	~43k	1 in 49	1 in 1,600
Remaining (unassigned)	~30k	1 in 76	1 in 4,300
European (Finnish)	~27k	1 in 440	≈ 1 in 8,900
Admixed American	~22k	1 in 93	≈ 1 in 11,000
African / African American	~21k	1 in 59	1 in 2,600
East Asian	~20k	1 in 63	1 in 2,600
Ashkenazi Jewish	~13k	1 in 240	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 73	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): 6 of 7 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 7.? see exons ↓