AMOTL1

Chr 11AD

angiomotin like 1

Also known as: CFCHS, JEAP

NCBI Gene: 154810 ENSG00000166025 UniProt: Q8IY63 OMIM: 614657

The protein is a peripheral membrane component of tight junctions that controls paracellular permeability and cell polarity, and also inhibits Wnt/beta-catenin signaling by preventing nuclear translocation of beta-catenin. Mutations cause autosomal recessive limb malformations-intellectual disability syndrome, characterized by developmental delays and limb defects. This gene is highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a peripheral membrane protein that is a component of tight junctions or TJs. TJs form an apical junctional structure and act to control paracellular permeability and maintain cell polarity. This protein is related to angiomotin, an angiostatin binding protein that regulates endothelial cell migration and capillary formation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Craniofaciocardiohepatic syndromeMIM #621192

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Craniofaciocardiohepatic syndrome; no ClinGen or GenCC tier

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.47

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.002

Z-score 4.41

OE 0.30 (0.20–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.22Z-score

OE missense 0.85 (0.79–0.92)

471 obs / 551.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.20–0.47)

0≤0.351.4

Missense OE?0.85 (0.79–0.92)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 14 / 46.4Missense obs/exp: 471 / 551.7Syn Z: 0.30

Background carrier burden — how many people carry a rare variant somewhere in AMOTL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 53

1,249 rare PASS variants

Rare truncating (LoF)

1 in 2,000

110 rare PASS variants

Rare synonymous (reference)

1 in 49

533 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AMOTL1. 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 71	1 in 2,000
South Asian	~43k	1 in 44	1 in 1,800
Remaining (unassigned)	~30k	1 in 39	1 in 2,800
European (Finnish)	~27k	1 in 130	1 in 3,000
Admixed American	~22k	1 in 34	1 in 1,300
African / African American	~21k	1 in 47	≈ 1 in 4,200
East Asian	~20k	1 in 49	1 in 870
Ashkenazi Jewish	~13k	1 in 120	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 38	≈ 1 in 1,200

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 13 coding exons well covered in gnomAD exomes and genomes.? see exons ↓