Hypocalcified amelogenesis imperfecta

disease

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Also known as amelogenesis imperfecta type 3

Summary

Hypocalcified amelogenesis imperfecta (MONDO:0968955) is a disease with 1 cohort gene.

At a glance

Cohort genes: 1
ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypocalcified amelogenesis imperfecta
Mondo ID	MONDO:0968955
Orphanet	100032
ICD-11	1793262466
UMLS	C0399376
MedGen	140773
GARD	0016931
Is cancer (heuristic)	no

Also known as: amelogenesis imperfecta type 3

Data availability: 19 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Subtypes (3): amelogenesis imperfecta, type 3A, amelogenesis imperfecta type 3B, amelogenesis imperfecta, type 3C

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

19 retrieved; paginated sample, class counts are floors:

12 pathogenic, 3 benign, 1 uncertain significance, 1 likely benign, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1192506	NM_198488.5(SACK1H):c.1309_1311delinsTAA (p.His437Ter)	SACK1H	Pathogenic	no assertion criteria provided
1192507	NM_198488.5(SACK1H):c.1828G>T (p.Glu610Ter)	SACK1H	Pathogenic	no assertion criteria provided
1192508	NM_198488.5(SACK1H):c.1330C>T (p.Gln444Ter)	SACK1H	Pathogenic	no assertion criteria provided
1192509	NM_198488.5(SACK1H):c.1915A>T (p.Lys639Ter)	SACK1H	Pathogenic	no assertion criteria provided
1299360	NM_198488.5(SACK1H):c.1363C>T (p.Gln455Ter)	SACK1H	Pathogenic	no assertion criteria provided
2445422	NM_198488.5(SACK1H):c.930_939dup (p.Val314fs)	SACK1H	Pathogenic	criteria provided, single submitter
2445424	NM_198488.5(SACK1H):c.1309_1311delinsTAG (p.His437Ter)	SACK1H	Pathogenic	criteria provided, single submitter
2445425	NM_198488.5(SACK1H):c.1375C>T (p.Gln459Ter)	SACK1H	Pathogenic	criteria provided, single submitter
488513	NM_198488.5(SACK1H):c.926_927del (p.Val309fs)	SACK1H	Pathogenic	criteria provided, single submitter
770	NM_198488.5(SACK1H):c.973C>T (p.Arg325Ter)	SACK1H	Pathogenic	criteria provided, single submitter
775	NM_198488.5(SACK1H):c.2029C>T (p.Gln677Ter)	SACK1H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
776	NM_198488.5(SACK1H):c.1408C>T (p.Gln470Ter)	SACK1H	Pathogenic	no assertion criteria provided
781	NM_198488.5(SACK1H):c.1379G>A (p.Trp460Ter)	SACK1H	Pathogenic	no assertion criteria provided
802444	NM_198488.5(SACK1H):c.1669G>T (p.Gly557Cys)	SACK1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2445450	NM_198488.5(SACK1H):c.1498C>G (p.Leu500Val)	SACK1H	Uncertain significance	criteria provided, single submitter
2503050	NM_198488.5(SACK1H):c.1466del (p.Phe489fs)	SACK1H	Likely benign	criteria provided, single submitter
263132	NM_198488.5(SACK1H):c.1493C>T (p.Pro498Leu)	SACK1H	Benign	criteria provided, multiple submitters, no conflicts
263133	NM_198488.5(SACK1H):c.1827C>T (p.Tyr609=)	SACK1H	Benign	criteria provided, multiple submitters, no conflicts
263135	NM_198488.5(SACK1H):c.2884C>T (p.Leu962=)	SACK1H	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SACK1H	Orphanet:100032	Hypocalcified 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
SACK1H	HGNC:24797	ENSG00000180921	Q6ZRV2	Protein FAM83H	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SACK1H	Protein FAM83H	May play a major role in the structural organization and calcification of developing enamel.

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)
SACK1H	Other/Unknown	no		SACK1, PLDc_FAM83H_N, FAM83

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
esophagus mucosa	1
lower esophagus mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SACK1H	128	ubiquitous	yes	lower esophagus mucosa, esophagus mucosa, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SACK1H	1,214

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SACK1H	Q6ZRV2	50.43

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 localization to cytoskeleton	1	8426.0×	6e-04	SACK1H
intermediate filament cytoskeleton organization	1	936.2×	0.003	SACK1H
biomineral tissue development	1	648.1×	0.003	SACK1H
positive regulation of cell migration	1	61.7×	0.020	SACK1H
signal transduction	1	16.1×	0.062	SACK1H

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
SACK1H	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	SACK1H

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)
SACK1H	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: SACK1H