palmoplantar keratoderma, punctate type 1A

Summary

palmoplantar keratoderma, punctate type 1A (MONDO:0007858) is a disease caused by AAGAB (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: AAGAB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	palmoplantar keratoderma, punctate type 1A
Mondo ID	MONDO:0007858
OMIM	148600
DOID	DOID:0080214
GARD	0015081
Is cancer (heuristic)	no

Also known as: AAGAB punctate palmoplantar keratoderma · keratoderma, palmoplantar, punctate type IA · palmoplantar keratoderma, punctate type 1A · palmoplantar keratoderma, punctate type IA · PPKP1A · punctate palmoplantar keratoderma caused by mutation in AAGAB

Data availability: 20 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › punctate palmoplantar keratoderma › punctate palmoplantar keratoderma type 1 › palmoplantar keratoderma, punctate type 1A

Related subtypes (1): palmoplantar keratoderma, punctate type ib

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

20 retrieved; paginated sample, class counts are floors:

9 pathogenic, 5 benign, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2155138	NM_024666.5(AAGAB):c.451+3_451+6del	AAGAB	Pathogenic	criteria provided, multiple submitters, no conflicts
3254572	NM_024666.5(AAGAB):c.31delinsGC (p.Thr11fs)	AAGAB	Pathogenic	criteria provided, single submitter
39732	NM_024666.5(AAGAB):c.481C>T (p.Arg161Ter)	AAGAB	Pathogenic	criteria provided, multiple submitters, no conflicts
39733	NM_024666.5(AAGAB):c.370C>T (p.Arg124Ter)	AAGAB	Pathogenic	criteria provided, multiple submitters, no conflicts
39734	NM_024666.5(AAGAB):c.348_349del (p.Arg116fs)	AAGAB	Pathogenic	no assertion criteria provided
39735	NM_024666.5(AAGAB):c.473del (p.Gly158fs)	AAGAB	Pathogenic	criteria provided, multiple submitters, no conflicts
39736	NM_024666.5(AAGAB):c.201_204del (p.Phe67fs)	AAGAB	Pathogenic	no assertion criteria provided
4686702	NM_024666.5(AAGAB):c.315G>A (p.Trp105Ter)	AAGAB	Pathogenic	criteria provided, single submitter
620111	NM_024666.5(AAGAB):c.61C>T (p.Gln21Ter)	AAGAB	Pathogenic	criteria provided, multiple submitters, no conflicts
1028839	NM_024666.5(AAGAB):c.870+1G>T	AAGAB	Likely pathogenic	criteria provided, single submitter
2431961	NM_024666.5(AAGAB):c.778G>T (p.Glu260Ter)	AAGAB	Likely pathogenic	criteria provided, single submitter
1510379	NM_024666.5(AAGAB):c.415G>A (p.Val139Ile)	AAGAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3631210	NM_024666.5(AAGAB):c.658T>C (p.Ser220Pro)	AAGAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3254952	NM_024666.5(AAGAB):c.451+2dup	AAGAB	Uncertain significance	criteria provided, single submitter
39737	NM_024666.5(AAGAB):c.870+1G>A	AAGAB	Uncertain significance	criteria provided, single submitter
1231574	NM_024666.5(AAGAB):c.264+33A>G	AAGAB	Benign	criteria provided, multiple submitters, no conflicts
1257765	NM_024666.5(AAGAB):c.619-37C>T	AAGAB	Benign	criteria provided, multiple submitters, no conflicts
1264407	NM_024666.5(AAGAB):c.536-95G>A	AAGAB	Benign	criteria provided, multiple submitters, no conflicts
1280017	NM_024666.5(AAGAB):c.618+18A>G	AAGAB	Benign	criteria provided, multiple submitters, no conflicts
803103	NM_024666.5(AAGAB):c.394A>C (p.Ile132Leu)	AAGAB	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
AAGAB	Definitive	Autosomal dominant	palmoplantar keratoderma, punctate type 1A	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AAGAB	Orphanet:79501	Punctate palmoplantar keratoderma type 1

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
AAGAB	HGNC:25662	ENSG00000103591	Q6PD74	Alpha- and gamma-adaptin-binding protein p34	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AAGAB	Alpha- and gamma-adaptin-binding protein p34	May be involved in endocytic recycling of growth factor receptors such as EGFR.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AAGAB	Other/Unknown	no		Alpha/Gamma-adaptin-bd_p34

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
islet of Langerhans	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AAGAB	282	ubiquitous	marker	islet of Langerhans, rectum, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AAGAB	931

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AAGAB	Q6PD74	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
protein transport	1	43.9×	0.023	AAGAB

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
AAGAB	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	AAGAB

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)
AAGAB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.