Maturity-onset diabetes of the young type 14

Summary

Maturity-onset diabetes of the young type 14 (MONDO:0014674) is a disease caused by APPL1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: APPL1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maturity-onset diabetes of the young type 14
Mondo ID	MONDO:0014674
OMIM	616511
DOID	DOID:0111111
UMLS	C4225299
MedGen	908119
GARD	0016128
Is cancer (heuristic)	no

Also known as: APPL1 maturity-onset diabetes of the young (disease) · maturity-onset diabetes of the young (disease) caused by mutation in APPL1 · maturity-onset diabetes of the young, type 14 · MODY14

Data availability: 18 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › monogenic diabetes › maturity-onset diabetes of the young › maturity-onset diabetes of the young type 14

Related subtypes (14): maturity-onset diabetes of the young type 1, maturity-onset diabetes of the young type 2, renal cysts and diabetes syndrome, maturity-onset diabetes of the young type 3, maturity-onset diabetes of the young type 4, maturity-onset diabetes of the young type 6, maturity-onset diabetes of the young type 8, maturity-onset diabetes of the young type 7, maturity-onset diabetes of the young type 9, maturity-onset diabetes of the young type 10, maturity-onset diabetes of the young type 11, Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young, maturity-onset diabetes of the young type 13, maturity-onset diabetes of the young, type 12

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

18 retrieved; paginated sample, class counts are floors:

6 benign/likely benign, 5 uncertain significance, 2 conflicting classifications of pathogenicity, 2 likely benign, 1 benign, 1 pathogenic, 1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
208074	NM_012096.3(APPL1):c.1655T>A (p.Leu552Ter)	APPL1	Pathogenic	no assertion criteria provided
1315697	NM_012096.3(APPL1):c.1930_1933del (p.Glu643_Arg644insTer)	APPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318138	NM_012096.3(APPL1):c.1961A>G (p.Asn654Ser)	APPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208075	NM_012096.3(APPL1):c.280G>A (p.Asp94Asn)	APPL1	no classifications from unflagged records	no classifications from unflagged records
2921225	NM_012096.3(APPL1):c.824G>A (p.Arg275Gln)	APPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3128079	NM_012096.3(APPL1):c.1694C>T (p.Thr565Met)	APPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3375279	NM_012096.3(APPL1):c.214C>T (p.Arg72Cys)	APPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3600418	NM_012096.3(APPL1):c.107A>G (p.Tyr36Cys)	APPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4128148	NM_012096.3(APPL1):c.1432C>T (p.Arg478Cys)	APPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1170466	NM_012096.3(APPL1):c.69A>G (p.Leu23=)	APPL1	Benign	criteria provided, multiple submitters, no conflicts
1183160	NM_012096.3(APPL1):c.36G>C (p.Thr12=)	APPL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1336005	NM_012096.3(APPL1):c.1262C>T (p.Pro421Leu)	APPL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1336573	NM_012096.3(APPL1):c.200A>G (p.Glu67Gly)	APPL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1678586	NM_012096.3(APPL1):c.1926A>G (p.Ile642Met)	APPL1	Likely benign	criteria provided, multiple submitters, no conflicts
2428706	NM_012096.3(APPL1):c.374-9C>T	APPL1	Likely benign	criteria provided, single submitter
712437	NM_012096.3(APPL1):c.1002C>G (p.Asp334Glu)	APPL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
713805	NM_012096.3(APPL1):c.256T>C (p.Leu86=)	APPL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
778086	NM_012096.3(APPL1):c.219T>C (p.Phe73=)	APPL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
APPL1	Strong	Autosomal dominant	maturity-onset diabetes of the young type 14	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APPL1	Orphanet:552	MODY

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APPL1	HGNC:24035	ENSG00000157500	Q9UKG1	DCC-interacting protein 13-alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APPL1	DCC-interacting protein 13-alpha	Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APPL1	Scaffold/PPI	no		PH_domain, BAR_dom, PTB/PI_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
calcaneal tendon	1
germinal epithelium of ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APPL1	284	ubiquitous	marker	calcaneal tendon, biceps brachii, germinal epithelium of ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APPL1	2,806

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APPL1	Q9UKG1	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Caspase activation via Dependence Receptors in the absence of ligand	1	1142.0×	9e-04	APPL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis	1	16852.0×	0.001	APPL1
positive regulation of macropinocytosis	1	8426.0×	0.001	APPL1
regulation of toll-like receptor 4 signaling pathway	1	5617.3×	0.001	APPL1
adiponectin-activated signaling pathway	1	2106.5×	0.002	APPL1
regulation of D-glucose import across plasma membrane	1	2106.5×	0.002	APPL1
signaling	1	1532.0×	0.002	APPL1
maintenance of synapse structure	1	1532.0×	0.002	APPL1
positive regulation of melanin biosynthetic process	1	1404.3×	0.002	APPL1
regulation of fibroblast migration	1	1296.3×	0.002	APPL1
cellular response to hepatocyte growth factor stimulus	1	1123.5×	0.002	APPL1
regulation of innate immune response	1	648.1×	0.002	APPL1
regulation of protein localization to plasma membrane	1	648.1×	0.002	APPL1
positive regulation of cytokine production involved in inflammatory response	1	543.6×	0.003	APPL1
positive regulation of D-glucose import across plasma membrane	1	455.5×	0.003	APPL1
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.004	APPL1
insulin receptor signaling pathway	1	221.7×	0.005	APPL1
transforming growth factor beta receptor signaling pathway	1	159.0×	0.007	APPL1
protein import into nucleus	1	144.0×	0.007	APPL1
signal transduction	1	16.1×	0.062	APPL1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APPL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APPL1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
APPL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.