amelogenesis imperfecta type 1G

Summary

amelogenesis imperfecta type 1G (MONDO:0008771) is a disease caused by FAM20A (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: FAM20A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 144
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta type 1G
Mondo ID	MONDO:0008771
MeSH	C538241
OMIM	204690, 614253
Orphanet	1031, 171836
DOID	DOID:0110066
SNOMED CT	109477002
UMLS	C2931783
MedGen	419162
GARD	0000646
Is cancer (heuristic)	no

Also known as: absent enamel, nephrocalcinosis and apparently normal calcium metabolism · AI1G · AIGFS · amelogenesis imperfecta and gingival fibromatosis syndrome · amelogenesis imperfecta and nephrocalcinosis · amelogenesis imperfecta caused by mutation in FAM20A · amelogenesis imperfecta hypoplastic type, IG · amelogenesis imperfecta nephrocalcinosis · amelogenesis imperfecta, type IG · amelogenesis imperfecta, type IG (enamel-renal syndrome) · amelogenesis imperfecta-gingival hyperplasia syndrome · enamel renal syndrome · enamel-renal syndrome · enamel-renal-gingival syndrome · ERS · ers · FAM20A amelogenesis imperfecta · generalised enamel hypoplasia and renal dysfunction · generalized enamel hypoplasia and renal dysfunction

Data availability: 144 ClinVar variants · 5 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 1G

Related subtypes (6): hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2, amelogenesis imperfecta type 1, amelogenesis imperfecta type 2, amelogenesis imperfecta, IIa 1K, hypocalcified amelogenesis imperfecta

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

144 retrieved; paginated sample, class counts are floors:

82 uncertain significance, 21 pathogenic, 17 likely pathogenic, 10 likely benign, 5 conflicting classifications of pathogenicity, 5 benign/likely benign, 2 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1189033	NM_017565.4(FAM20A):c.[129del;734_735del]		Pathogenic	no assertion criteria provided
1029473	NM_017565.4(FAM20A):c.915_918del (p.Phe305fs)	FAM20A	Pathogenic	criteria provided, multiple submitters, no conflicts
1240402	NM_017565.4(FAM20A):c.111_145del (p.Glu39fs)	FAM20A	Pathogenic	criteria provided, single submitter
1322863	NM_017565.4(FAM20A):c.349_367del (p.Leu117fs)	FAM20A	Pathogenic	criteria provided, multiple submitters, no conflicts
1371040	NM_017565.4(FAM20A):c.721C>T (p.Gln241Ter)	FAM20A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
139648	NM_017565.4(FAM20A):c.720-2A>G	FAM20A	Pathogenic	criteria provided, single submitter
139649	NM_017565.4(FAM20A):c.1432C>T (p.Arg478Ter)	FAM20A	Pathogenic	no assertion criteria provided
139650	NM_017565.4(FAM20A):c.612del (p.Leu205fs)	FAM20A	Pathogenic	no assertion criteria provided
1691422	NM_017565.4(FAM20A):c.1109+3_1109+7delinsTGGTC	FAM20A	Pathogenic	criteria provided, single submitter
1691825	NC_000017.11:g.68534268_68541798del	FAM20A	Pathogenic	criteria provided, single submitter
1696930	NM_017565.4(FAM20A):c.1447del (p.Glu483fs)	FAM20A	Pathogenic	criteria provided, multiple submitters, no conflicts
2723208	NM_017565.4(FAM20A):c.907_908del (p.Ser303fs)	FAM20A	Pathogenic	criteria provided, multiple submitters, no conflicts
30879	NM_017565.4(FAM20A):c.406C>T (p.Arg136Ter)	FAM20A	Pathogenic	criteria provided, multiple submitters, no conflicts
3242586	NM_017565.4(FAM20A):c.188dup (p.Asp63fs)	FAM20A	Pathogenic	no assertion criteria provided
35475	NM_017565.4(FAM20A):c.34_35del (p.Leu12fs)	FAM20A	Pathogenic	no assertion criteria provided
35476	NM_017565.4(FAM20A):c.813-2A>G	FAM20A	Pathogenic	criteria provided, multiple submitters, no conflicts
35477	NM_017565.4(FAM20A):c.1175_1179del (p.Arg392fs)	FAM20A	Pathogenic	no assertion criteria provided
35478	NM_017565.4(FAM20A):c.590-2A>G	FAM20A	Pathogenic	no assertion criteria provided
35479	NM_017565.4(FAM20A):c.826C>T (p.Arg276Ter)	FAM20A	Pathogenic	criteria provided, single submitter
3582760	NM_017565.4(FAM20A):c.727C>T (p.Arg243Ter)	FAM20A	Pathogenic	criteria provided, single submitter
3582767	NM_017565.4(FAM20A):c.590-5T>A	FAM20A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3582770	NM_017565.4(FAM20A):c.466C>T (p.Arg156Ter)	FAM20A	Pathogenic	criteria provided, single submitter
4845821	NM_017565.4(FAM20A):c.1481_1482dup (p.Leu495fs)	FAM20A	Pathogenic	criteria provided, single submitter
1691423	NM_017565.4(FAM20A):c.1231C>T (p.Arg411Trp)	FAM20A	Likely pathogenic	criteria provided, single submitter
1691824	NM_017565.4(FAM20A):c.758A>G (p.Tyr253Cys)	FAM20A	Likely pathogenic	criteria provided, single submitter
2445460	NM_017565.4(FAM20A):c.610del (p.Ala204fs)	FAM20A	Likely pathogenic	criteria provided, single submitter
2445463	NM_017565.4(FAM20A):c.1361+1G>A	FAM20A	Likely pathogenic	criteria provided, single submitter
2445596	NM_017565.4(FAM20A):c.928+2T>C	FAM20A	Likely pathogenic	criteria provided, single submitter
2664908	NM_017565.4(FAM20A):c.626dup (p.Cys209fs)	FAM20A	Likely pathogenic	criteria provided, single submitter
3351868	NM_017565.4(FAM20A):c.752TCT[1] (p.Phe252del)	FAM20A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
FAM20A	Definitive	Autosomal recessive	amelogenesis imperfecta type 1G	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAM20A	Orphanet:1031	Enamel-renal syndrome
PRKAR1A	Orphanet:1359	Carney complex
PRKAR1A	Orphanet:1501	Adrenocortical carcinoma
PRKAR1A	Orphanet:520	Acute promyelocytic leukemia
PRKAR1A	Orphanet:615	Familial atrial myxoma
PRKAR1A	Orphanet:647772	Isolated primary pigmented nodular adrenocortical disease
PRKAR1A	Orphanet:950	Acrodysostosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FAM20A	HGNC:23015	ENSG00000108950	Q96MK3	Pseudokinase FAM20A	gencc,clinvar
PRKAR1A	HGNC:9388	ENSG00000108946	P10644	cAMP-dependent protein kinase type I-alpha regulatory subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAM20A	Pseudokinase FAM20A	Pseudokinase that acts as an allosteric activator of the Golgi serine/threonine protein kinase FAM20C and is involved in biomineralization of teeth.
PRKAR1A	cAMP-dependent protein kinase type I-alpha regulatory subunit	Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAM20A	Other/Unknown	no		FAM20_C, FAM20
PRKAR1A	Other/Unknown	no		cNMP-bd_dom, cAMP_dep_PK_reg_su_I/II_a/b, cAMP_dep_PK_reg_su

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	1
smooth muscle tissue	1
upper lobe of left lung	1
germinal epithelium of ovary	1
lateral nuclear group of thalamus	1
mucosa of paranasal sinus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAM20A	196	broad	marker	right lobe of liver, smooth muscle tissue, upper lobe of left lung
PRKAR1A	295	ubiquitous	marker	mucosa of paranasal sinus, germinal epithelium of ovary, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAR1A	3,586
FAM20A	736

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAM20A	Q96MK3	4
PRKAR1A	P10644	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ALK mutants bind TKIs	1	475.8×	0.017	PRKAR1A
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	439.2×	0.017	PRKAR1A
PKA activation in glucagon signalling	1	335.9×	0.017	PRKAR1A
PKA activation	1	317.2×	0.017	PRKAR1A
PKA-mediated phosphorylation of CREB	1	285.5×	0.017	PRKAR1A
DARPP-32 events	1	237.9×	0.017	PRKAR1A
Anti-inflammatory response favouring Leishmania parasite infection	1	196.9×	0.017	PRKAR1A
Leishmania parasite growth and survival	1	196.9×	0.017	PRKAR1A
Calmodulin induced events	1	190.3×	0.017	PRKAR1A
CaM pathway	1	190.3×	0.017	PRKAR1A
Ca-dependent events	1	184.2×	0.017	PRKAR1A
Aquaporin-mediated transport	1	184.2×	0.017	PRKAR1A
Glucagon signaling in metabolic regulation	1	173.0×	0.017	PRKAR1A
G-protein mediated events	1	163.1×	0.017	PRKAR1A
DAG and IP3 signaling	1	158.6×	0.017	PRKAR1A
Response of endothelial cells to shear stress	1	150.3×	0.017	PRKAR1A
FCGR3A-mediated IL10 synthesis	1	146.4×	0.017	PRKAR1A
Signaling by ALK in cancer	1	135.9×	0.017	PRKAR1A
Opioid Signalling	1	132.8×	0.017	PRKAR1A
PLC beta mediated events	1	132.8×	0.017	PRKAR1A
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	132.8×	0.017	PRKAR1A
Vasopressin regulates renal water homeostasis via Aquaporins	1	132.8×	0.017	PRKAR1A
Cellular responses to mechanical stimuli	1	129.8×	0.017	PRKAR1A
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.017	PRKAR1A
GPER1 signaling	1	124.1×	0.017	PRKAR1A
Regulation of insulin secretion	1	109.8×	0.019	PRKAR1A
Post NMDA receptor activation events	1	102.0×	0.020	PRKAR1A
Activation of NMDA receptors and postsynaptic events	1	92.1×	0.020	PRKAR1A
Signaling by Hedgehog	1	92.1×	0.020	PRKAR1A
Hedgehog ‘off’ state	1	89.2×	0.020	PRKAR1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tooth eruption	1	1685.2×	0.008	FAM20A
enamel mineralization	1	601.9×	0.008	FAM20A
negative regulation of activated T cell proliferation	1	526.6×	0.008	PRKAR1A
cellular response to glucagon stimulus	1	421.3×	0.008	PRKAR1A
vascular endothelial cell response to laminar fluid shear stress	1	366.4×	0.008	PRKAR1A
biomineral tissue development	1	324.1×	0.008	FAM20A
negative regulation of inflammatory response to antigenic stimulus	1	300.9×	0.008	PRKAR1A
negative regulation of cAMP/PKA signal transduction	1	300.9×	0.008	PRKAR1A
cardiac muscle cell proliferation	1	290.6×	0.008	PRKAR1A
renal water homeostasis	1	255.3×	0.008	PRKAR1A
mesoderm formation	1	247.8×	0.008	PRKAR1A
calcium ion homeostasis	1	221.7×	0.008	FAM20A
sarcomere organization	1	191.5×	0.008	PRKAR1A
positive regulation of protein phosphorylation	1	138.1×	0.011	FAM20A
positive regulation of insulin secretion	1	127.7×	0.011	PRKAR1A
response to bacterium	1	96.8×	0.014	FAM20A
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.022	PRKAR1A
chemical synaptic transmission	1	38.6×	0.030	PRKAR1A
negative regulation of gene expression	1	34.5×	0.032	PRKAR1A
intracellular signal transduction	1	19.1×	0.054	PRKAR1A
regulation of transcription by RNA polymerase II	1	5.8×	0.164	PRKAR1A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FAM20A	0	0
PRKAR1A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PRKAR1A	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	FAM20A, PRKAR1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FAM20A	0	—
PRKAR1A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07285421	Not specified	NOT_YET_RECRUITING	Renal and Vascular Phenotypic Characterization of Patients With Enamel Renal Syndrome Due to a Pathogenic Variant of the FAM20A Gene and Pathophysiological Study of Ectopic Calcifications