Isolated microphthalmia 8

Summary

Isolated microphthalmia 8 (MONDO:0014050) is a disease caused by ALDH1A3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ALDH1A3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 67

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated microphthalmia 8
Mondo ID	MONDO:0014050
OMIM	615113
DOID	DOID:0060841
UMLS	C3554524
MedGen	767438
GARD	0024967
Is cancer (heuristic)	no

Also known as: ALDH1A3 isolated microphthalmia · isolated microphthalmia 8 · isolated microphthalmia caused by mutation in ALDH1A3 · isolated microphthalmia type 8 · MCOP8 · microphthalmia, isolated 8 · microphthalmia, isolated type 8

Data availability: 67 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › isolated microphthalmia › isolated microphthalmia 8

Related subtypes (9): microphthalmia, isolated, with coloboma, microphthalmia, isolated, with cataract 1, isolated microphthalmia 1, isolated microphthalmia 2, isolated microphthalmia 3, isolated microphthalmia 5, isolated microphthalmia 4, isolated microphthalmia 6, isolated microphthalmia 7

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

67 retrieved; paginated sample, class counts are floors:

26 likely benign, 11 uncertain significance, 9 benign, 8 likely pathogenic, 8 pathogenic, 3 benign/likely benign, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1372977	NM_000693.4(ALDH1A3):c.439_458del (p.Trp147fs)	ALDH1A3	Pathogenic	criteria provided, single submitter
1801374	NM_000693.4(ALDH1A3):c.550del (p.Leu184fs)	ALDH1A3	Pathogenic	criteria provided, single submitter
1803002	NM_000693.4(ALDH1A3):c.566G>A (p.Trp189Ter)	ALDH1A3	Pathogenic	criteria provided, single submitter
1803003	NM_000693.4(ALDH1A3):c.100-2A>G	ALDH1A3	Pathogenic	criteria provided, single submitter
1803004	NM_000693.4(ALDH1A3):c.1233+2T>C	ALDH1A3	Pathogenic	criteria provided, single submitter
40203	NM_000693.4(ALDH1A3):c.265C>T (p.Arg89Cys)	ALDH1A3	Pathogenic	no assertion criteria provided
40204	NM_000693.4(ALDH1A3):c.1477G>C (p.Ala493Pro)	ALDH1A3	Pathogenic	no assertion criteria provided
40205	NM_000693.4(ALDH1A3):c.475+1G>T	ALDH1A3	Pathogenic	no assertion criteria provided
1049955	NM_000693.4(ALDH1A3):c.845G>T (p.Gly282Val)	ALDH1A3	Likely pathogenic	criteria provided, single submitter
1802995	NM_000693.4(ALDH1A3):c.1144G>A (p.Gly382Arg)	ALDH1A3	Likely pathogenic	criteria provided, single submitter
1802996	NM_000693.4(ALDH1A3):c.434C>T (p.Ala145Val)	ALDH1A3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802998	NM_000693.4(ALDH1A3):c.845G>C (p.Gly282Ala)	ALDH1A3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802999	NM_000693.4(ALDH1A3):c.1459A>G (p.Arg487Gly)	ALDH1A3	Likely pathogenic	criteria provided, single submitter
3064143	NM_000693.4(ALDH1A3):c.1105A>T (p.Ile369Phe)	ALDH1A3	Likely pathogenic	criteria provided, single submitter
3777064	NM_000693.4(ALDH1A3):c.172dup (p.Glu58fs)	ALDH1A3	Likely pathogenic	criteria provided, single submitter
4279036	NM_000693.4(ALDH1A3):c.1334C>T (p.Thr445Ile)	ALDH1A3	Likely pathogenic	criteria provided, single submitter
429799	NM_000693.4(ALDH1A3):c.845G>A (p.Gly282Glu)	ALDH1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800192	NM_000693.4(ALDH1A3):c.1306G>A (p.Asp436Asn)	ALDH1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333588	NM_000693.4(ALDH1A3):c.884-2_885dup	ALDH1A3	Uncertain significance	criteria provided, single submitter
1426156	NM_000693.4(ALDH1A3):c.617C>T (p.Ala206Val)	ALDH1A3	Uncertain significance	criteria provided, single submitter
1802994	NM_000693.4(ALDH1A3):c.874G>T (p.Asp292Tyr)	ALDH1A3	Uncertain significance	criteria provided, single submitter
1802997	NM_000693.4(ALDH1A3):c.1393A>T (p.Ile465Phe)	ALDH1A3	Uncertain significance	criteria provided, single submitter
1803000	NM_000693.4(ALDH1A3):c.847_849del (p.Gly283del)	ALDH1A3	Uncertain significance	criteria provided, single submitter
1803001	NM_000693.4(ALDH1A3):c.953C>A (p.Ser318Tyr)	ALDH1A3	Uncertain significance	criteria provided, single submitter
1954065	NM_000693.4(ALDH1A3):c.361G>A (p.Asp121Asn)	ALDH1A3	Uncertain significance	criteria provided, single submitter
2690875	NM_000693.4(ALDH1A3):c.865G>A (p.Val289Met)	ALDH1A3	Uncertain significance	criteria provided, single submitter
3707197	NM_000693.4(ALDH1A3):c.191AAG[1] (p.Glu65del)	ALDH1A3	Uncertain significance	criteria provided, single submitter
652391	NC_000015.9:g.(?101420093)(101454998_?)dup	ALDH1A3	Uncertain significance	criteria provided, single submitter
653567	NM_000693.4(ALDH1A3):c.964G>A (p.Val322Met)	ALDH1A3	Uncertain significance	criteria provided, single submitter
1117734	NM_000693.4(ALDH1A3):c.538-4G>A	ALDH1A3	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
ALDH1A3	Definitive	Autosomal recessive	isolated anophthalmia-microphthalmia syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH1A3	Orphanet:35612	Nanophthalmos
ALDH1A3	Orphanet:98938	Colobomatous microphthalmia

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH1A3	HGNC:409	ENSG00000184254	P47895	Retinaldehyde dehydrogenase 3	gencc,clinvar
ALDH1A3-AS1	HGNC:55416	ENSG00000259583		ALDH1A3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH1A3	Retinaldehyde dehydrogenase 3	Catalyzes the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH1A3	Enzyme (other)	yes	1.2.1.5	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH
ALDH1A3-AS1	Other/Unknown	no

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
palpebral conjunctiva	1
parietal pleura	1
pigmented layer of retina	1
minor salivary gland	1
prostate gland	1
saliva-secreting gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH1A3	244	ubiquitous	marker	palpebral conjunctiva, pigmented layer of retina, parietal pleura
ALDH1A3-AS1	132	tissue_specific	marker	minor salivary gland, saliva-secreting gland, prostate gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH1A3	4,146
ALDH1A3-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH1A3	P47895	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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
Developmental Lineage of Mammary Stem Cells	1	761.3×	0.003	ALDH1A3
Developmental Lineage of Mammary Gland Alveolar Cells	1	634.4×	0.003	ALDH1A3
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.003	ALDH1A3
RA biosynthesis pathway	1	475.8×	0.003	ALDH1A3
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	456.8×	0.003	ALDH1A3
Signaling by Retinoic Acid	1	407.9×	0.003	ALDH1A3
Signaling by Nuclear Receptors	1	102.0×	0.011	ALDH1A3
Signal Transduction	1	10.2×	0.098	ALDH1A3

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
nucleus accumbens development	1	16852.0×	0.001	ALDH1A3
optic cup morphogenesis involved in camera-type eye development	1	8426.0×	0.001	ALDH1A3
olfactory pit development	1	5617.3×	0.001	ALDH1A3
retinoic acid biosynthetic process	1	4213.0×	0.001	ALDH1A3
Harderian gland development	1	3370.4×	0.001	ALDH1A3
righting reflex	1	1872.4×	0.002	ALDH1A3
embryonic eye morphogenesis	1	1532.0×	0.002	ALDH1A3
aldehyde metabolic process	1	1296.3×	0.002	ALDH1A3
embryonic camera-type eye development	1	1203.7×	0.002	ALDH1A3
retinal metabolic process	1	936.2×	0.002	ALDH1A3
retinoic acid metabolic process	1	802.5×	0.002	ALDH1A3
face development	1	802.5×	0.002	ALDH1A3
retinol metabolic process	1	495.6×	0.003	ALDH1A3
neuromuscular process controlling balance	1	330.4×	0.004	ALDH1A3
inner ear morphogenesis	1	300.9×	0.004	ALDH1A3
protein homotetramerization	1	237.3×	0.005	ALDH1A3
locomotory behavior	1	179.3×	0.006	ALDH1A3
positive regulation of apoptotic process	1	56.7×	0.019	ALDH1A3
apoptotic process	1	28.7×	0.035	ALDH1A3

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
ALDH1A3	0	0
ALDH1A3-AS1	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
ALDH1A3	55	Binding:55

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH1A3	1.2.1.5	aldehyde dehydrogenase [NAD(P)+]

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	ALDH1A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ALDH1A3-AS1

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)
ALDH1A3	55	—
ALDH1A3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.