ANK3

Chr 10AR

ankyrin 3

Also known as: ANKYRIN-G, MRT37

NCBI Gene: 288 ENSG00000151150 UniProt: Q12955 OMIM: 600465

Ankyrin-3 is a membrane-cytoskeleton linker protein that localizes ion channels and cell adhesion molecules at axonal initial segments and nodes of Ranvier in neurons. Mutations cause autosomal recessive intellectual developmental disorder. This gene is highly constrained against loss-of-function variants (pLI=1, LOEUF=0.089), indicating that complete loss of ankyrin-3 function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 37MIM #615493

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · intellectual disability · AR · 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

0.09

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 11.22

OE 0.05 (0.03–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.79Z-score

OE missense 0.84 (0.81–0.87)

1928 obs / 2305.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.03–0.09)

0≤0.351.4

Missense OE?0.84 (0.81–0.87)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 8 / 162.2Missense obs/exp: 1928 / 2305.5Syn Z: -0.66

Background carrier burden — how many people carry a rare variant somewhere in ANK3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 12

5,316 rare PASS variants

Rare truncating (LoF)

1 in 640

231 rare PASS variants

Rare synonymous (reference)

1 in 22

2,217 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ANK3. 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 17	1 in 930
South Asian	~43k	1 in 10	1 in 560
Remaining (unassigned)	~30k	1 in 12	1 in 560
European (Finnish)	~27k	1 in 39	1 in 980
Admixed American	~22k	1 in 12	1 in 850
African / African American	~21k	1 in 12	1 in 1,200
East Asian	~20k	1 in 14	1 in 450
Ashkenazi Jewish	~13k	1 in 45	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 14	1 in 520

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): 32 of 43 coding exons well covered in gnomAD exomes; exons 2, 8, 11, 13, 15 and 6 more marginal. Genomes: all 43.? see exons ↓