PICALM

Chr 11

phosphatidylinositol binding clathrin assembly protein

Also known as: CALM, CLTH, LAP

NCBI Gene: 8301 ENSG00000073921 UniProt: Q13492 OMIM: 603025

This protein is a cytoplasmic adapter that recruits clathrin and AP-2 to plasma membranes for clathrin-mediated endocytosis and regulates clathrin-coated vesicle size and maturation, playing critical roles in synaptic transmission and autophagy. Somatic mutations cause acute myeloid leukemia, while the gene is highly constrained against loss-of-function variants in the general population. The gene shows autosomal inheritance patterns for constitutional variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a clathrin assembly protein, which recruits clathrin and adaptor protein complex 2 (AP2) to cell membranes at sites of coated-pit formation and clathrin-vesicle assembly. The protein may be required to determine the amount of membrane to be recycled, possibly by regulating the size of the clathrin cage. The protein is involved in AP2-dependent clathrin-mediated endocytosis at the neuromuscular junction. A chromosomal translocation t(10;11)(p13;q14) leading to the fusion of this gene and the MLLT10 gene is found in acute lymphoblastic leukemia, acute myeloid leukemia and malignant lymphomas. The polymorphisms of this gene are associated with the risk of Alzheimer disease. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Leukemia, acute myeloid, somaticMIM #601626

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Leukemia, acute myeloid, somatic; 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.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 0.999

Z-score 4.85

OE 0.09 (0.04–0.23)

Highly constrained

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

Missense Constraint?

1.45Z-score

OE missense 0.78 (0.70–0.86)

258 obs / 332.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.23)

0≤0.351.4

Missense OE?0.78 (0.70–0.86)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 3 / 33.1Missense obs/exp: 258 / 332.5Syn Z: -0.67

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

772 rare PASS variants

Rare truncating (LoF)

1 in 3,300

89 rare PASS variants

Rare synonymous (reference)

1 in 160

308 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PICALM. 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 130	1 in 3,700
South Asian	~43k	1 in 98	1 in 7,100
Remaining (unassigned)	~30k	1 in 95	1 in 6,000
European (Finnish)	~27k	1 in 180	1 in 2,600
Admixed American	~22k	1 in 74	≈ 1 in 5,100
African / African American	~21k	1 in 130	1 in 1,900
East Asian	~20k	1 in 88	≈ 1 in 6,500
Ashkenazi Jewish	~13k	1 in 270	1 in 640
Middle Eastern	~2,884	1 in 81	≈ 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): 8 of 20 coding exons well covered in gnomAD exomes; exon 8 poorly covered; exons 3, 4, 5, 6, 7 and 6 more marginal. Genomes: all 20.? see exons ↓