amelogenesis imperfecta type 2A1

Summary

amelogenesis imperfecta type 2A1 (MONDO:0008772) is a disease caused by KLK4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KLK4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta type 2A1
Mondo ID	MONDO:0008772
MeSH	C538242, C567146
OMIM	204700
DOID	DOID:0110057
UMLS	C2673922
MedGen	436039
GARD	0009495
Is cancer (heuristic)	no

Also known as: AI2A1 · amelogenesis imperfecta caused by mutation in KLK4 · amelogenesis imperfecta pigmented hypomaturation type · amelogenesis imperfecta, hypomaturation type, IIA1 · amelogenesis imperfecta, pigmented hypomaturation type, 1 · amelogenesis imperfecta, type IIA1 · KLK4 amelogenesis imperfecta

Data availability: 6 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › amelogenesis imperfecta › amelogenesis imperfecta type 2 › amelogenesis imperfecta type 2A1

Related subtypes (6): amelogenesis imperfecta type 1E, amelogenesis imperfecta hypomaturation type 2A2, amelogenesis imperfecta hypomaturation type 2A3, amelogenesis imperfecta hypomaturation type 2A4, amelogenesis imperfecta hypomaturation type 2A5, amelogenesis imperfecta, hypomaturation type, IIa6

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

6 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
189294	NM_004917.5(KLK4):c.245del (p.Gly82fs)	KLK4	Pathogenic	no assertion criteria provided
288110	NM_004917.5(KLK4):c.632del (p.Leu211fs)	KLK4	Pathogenic	criteria provided, multiple submitters, no conflicts
1299354	NM_004917.5(KLK4):c.620_621del (p.Ser207fs)	KLK4	Likely pathogenic	criteria provided, single submitter
3065689	NM_004917.5(KLK4):c.224+2T>C	KLK4	Likely pathogenic	criteria provided, single submitter
6079	NM_004917.5(KLK4):c.458G>A (p.Trp153Ter)	KLK4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445594	NM_004917.5(KLK4):c.443G>T (p.Cys148Phe)	KLK4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
KLK4	Strong	Autosomal recessive	amelogenesis imperfecta type 2A1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KLK4	Orphanet:100033	Hypomaturation amelogenesis imperfecta

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
KLK4	HGNC:6365	ENSG00000167749	Q9Y5K2	Kallikrein-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLK4	Kallikrein-4	Has a major role in enamel formation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KLK4	Protease	yes	3.4.21.B12	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA

Expression context

Cohort genes with no expression data: 0.

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
kidney epithelium	1
lower esophagus mucosa	1
prostate gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLK4	160	tissue_specific	yes	prostate gland, lower esophagus mucosa, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLK4	1,632

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLK4	Q9Y5K2	18

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
amelogenesis	1	1404.3×	0.004	KLK4
biomineral tissue development	1	648.1×	0.004	KLK4
extracellular matrix disassembly	1	366.4×	0.005	KLK4
protein maturation	1	163.6×	0.008	KLK4
proteolysis	1	34.2×	0.029	KLK4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KLK4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KLK4	13	Binding:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KLK4	3.4.21.B12

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	1	KLK4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
KLK4	13	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.