AKAP12

Chr 6

A-kinase anchoring protein 12

Also known as: AKAP250, SSeCKS

NCBI Gene: 9590ENSG00000131016UniProt: Q02952

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. The encoded protein is expressed in endothelial cells, cultured fibroblasts, and osteosarcoma cells. It associates with protein kinases A and C and phosphatase, and serves as a scaffold protein in signal transduction. This protein and RII PKA colocalize at the cell periphery. This protein is a cell growth-related protein. Antibodies to this protein can be produced by patients with myasthenia gravis. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

302
ClinVar variants
21
Pathogenic / LP
0.04
pLI score
1
Active trials
Clinical Summary— AKAP12
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
21 Pathogenic / Likely Pathogenic· 245 VUS of 302 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.43LOEUF
pLI 0.036
Z-score 4.61
OE 0.26 (0.17–0.43)
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.
0.57Z-score
OE missense 0.95 (0.90–1.00)
882 obs / 931.4 exp
Tolerant

Mild missense constraint

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.0.26 (0.17–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.90–1.00)
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.1.01
0≤1.21.6
LoF obs/exp: 12 / 45.6Missense obs/exp: 882 / 931.4Syn Z: -0.13

ClinVar Variant Classifications

302 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic1
VUS245
Likely Benign22
Benign12
Conflicting2
20
Pathogenic
1
Likely Pathogenic
245
VUS
22
Likely Benign
12
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
20
0
20
Likely Pathogenic
0
0
1
0
1
VUS
0
241
4
0
245
Likely Benign
0
20
0
2
22
Benign
0
5
1
6
12
Conflicting
—2
Total0266268302

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

View in ClinVar →

Protein Context — Lollipop Plot

AKAP12 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
AKAP12 positive fibroblast determines immunosuppressive contexture and immunotherapy response in patients with TNBC by promoting macrophage M2 polarization.
Liu Z et al.·J Immunother Cancer
2024Cohort
AKAP12 and RNF11 as Diagnostic Markers of Fibromyalgia and Their Correlation with Immune Infiltration.
Lin X et al.·Oxid Med Cell Longev
2022
HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance.
Robinson EL et al.·J Clin Invest
2023
AKAP12 Signaling Complex: Impacts of Compartmentalizing cAMP-Dependent Signaling Pathways in the Heart and Various Signaling Systems.
Qasim H et al.·J Am Heart Assoc
2020Review
AKAP12/Gravin is over-expressed in patients with ulcerative colitis.
Fonseca-Camarillo G et al.·Immunol Res
2021Cohort
Ubiquitin-related gene markers predict immunotherapy response and prognosis in patients with epithelial ovarian carcinoma.
Luo D et al.·Sci Rep
2024Cohort
AKAP12 Variant 1 Knockout Enhances Vascular Endothelial Cell Motility.
Ali A et al.·J Vasc Res
2025
Construction and validation of a prognostic model of angiogenesis-related genes in multiple myeloma.
Hu R et al.·BMC Cancer
2024Functional
Comprehensive Analysis of the Immune Implication of AKAP12 in Stomach Adenocarcinoma.
Xu Z et al.·Comput Math Methods Med
2022
Development and validation of a 16-gene T-cell- related prognostic model in non-small cell lung cancer.
Zhang A et al.·Front Immunol
2025Functional
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
Barrett EsophagusEsophageal CancerGastric Cancer

EsophaCap for the Detection of Early Esophageal Carcinoma

RECRUITING
NCT04214119Johns Hopkins UniversityStarted 2016-01-12

External Resources

Links to major genomics databases and tools