AKAP9

Chr 7AD

A-kinase anchoring protein 9

Also known as: AKAP-9, AKAP350, AKAP450, CG-NAP, HYPERION, LQT11, MU-RMS-40.16A, PPP1R45

NCBI Gene: 10142ENSG00000127914UniProt: Q99996

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternate splicing of this gene results in at least two isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3. [provided by RefSeq, Aug 2008]

Primary Disease Associations & Inheritance

?Long QT syndrome 11MIM #611820
AD
454
ClinVar variants
1
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— AKAP9
🧬
Gene-Disease Validity (ClinGen)
long QT syndrome · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
1 Pathogenic / Likely Pathogenic· 287 VUS of 454 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.40LOEUF
pLI 0.000
Z-score 9.06
OE 0.33 (0.27–0.40)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.13Z-score
OE missense 1.01 (0.97–1.05)
1850 obs / 1834.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.33 (0.27–0.40)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.97–1.05)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 71 / 214.0Missense obs/exp: 1850 / 1834.6Syn Z: 0.76

ClinVar Variant Classifications

454 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1
VUS287
Likely Benign165
Benign1
1
Likely Pathogenic
287
VUS
165
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
0
1
0
1
VUS
9
256
17
5
287
Likely Benign
0
23
39
103
165
Benign
0
1
0
0
1
Total928057108454

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

AKAP9 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AKAP9-related long QT syndrome

disputed
ADUndeterminedUncertain
Cardiac
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Long QT syndrome 11

MIM #611820

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Integrative proteogenomic characterization of early esophageal cancer.
Li L et al.·Nat Commun
2023
An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.
Adler A et al.·Circulation
2020
AKAP9-Related Channelopathy: Novel Pathogenic Variant and Review of the Literature.
Huynh MT et al.·Genes (Basel)
2022Review
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory.
Lieve KV et al.·Genet Test Mol Biomarkers
2013Cohort
Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis.
Frank B et al.·J Natl Cancer Inst
2008Meta-analysis
Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility.
Suárez-Rama JJ et al.·J Psychiatr Res
2015Meta-analysis
MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation.
Chodisetty S et al.·Sci Adv
2024
BRAF mutation and AKAP9 expression in sporadic papillary thyroid carcinomas.
Lee JH et al.·Pathology
2006
Alzheimer's disease: rare variants with large effect sizes.
Del-Aguila JL et al.·Curr Opin Genet Dev
2015Review
Unclassified sclerosing malignant melanomas with AKAP9-BRAF gene fusion: a report of two cases and review of BRAF fusions in melanocytic tumors.
Perron E et al.·Virchows Arch
2018Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Leber Congenital Amaurosis 10BlindnessLeber Congenital Amaurosis

Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)

RECRUITING
NCT06891443Phase PHASE3Laboratoires TheaStarted 2025-06-04
sepofarsenPlacebo IVT
Esophageal Squamous Cell Carcinoma

Pembrolizumab Plus Chemo in Neoadjuvant Treatment of Esophageal Squamous Cell Carcinoma (Eastern Cooperative Thoracic Oncology Projects 2004, ECTOP-2004)

RECRUITING
NCT05281003Phase PHASE2Fudan UniversityStarted 2023-02-20
PembrolizumabPaclitaxelCisplatin

External Resources

Links to major genomics databases and tools