Foveal hypoplasia 1

Summary

Foveal hypoplasia 1 (MONDO:0007628) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 122

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	foveal hypoplasia 1
Mondo ID	MONDO:0007628
OMIM	136520
DOID	DOID:0070530
UMLS	C3805604
MedGen	811934
GARD	0024566
Is cancer (heuristic)	no

Also known as: foveal hypoplasia 1 · foveal hypoplasia caused by mutation in PAX6 · foveal hypoplasia type 1 · foveal hypoplasia, congenital nystagmus, corneal pannus, and presenile cataracts · foveal hypoplasia, presenile cataract · FVH1 · O Donnell Pappas syndrome · PAX6 foveal hypoplasia

Data availability: 122 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › foveal hypoplasia › foveal hypoplasia 1

Related subtypes (3): foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, GPR143-related foveal hypoplasia, foveal hypoplasia 3

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

122 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 23 conflicting classifications of pathogenicity, 13 benign/likely benign, 12 benign, 5 pathogenic/likely pathogenic, 3 likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3474	NM_001368894.2(PAX6):c.1310A>T (p.Ter437Leu)	ELP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372441	NM_001368894.2(PAX6):c.664C>T (p.Arg222Trp)	ELP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279862	NM_001368894.2(PAX6):c.823C>T (p.Arg275Ter)	PAX6	Pathogenic	criteria provided, multiple submitters, no conflicts
3470	NM_001368894.2(PAX6):c.424C>T (p.Arg142Cys)	PAX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3471	NM_001368894.2(PAX6):c.419T>A (p.Val140Asp)	PAX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637045	NM_001368894.2(PAX6):c.112C>G (p.Arg38Gly)	PAX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3479	NM_001368894.2(PAX6):c.10+5G>C	PAX6	Likely pathogenic	criteria provided, single submitter
304291	NM_000280.4(PAX6):c.*4696G>C	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304292	NM_000280.4(PAX6):c.*4627A>C	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304304	NM_000280.4(PAX6):c.*3746C>T	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304307	NM_000280.4(PAX6):c.*3670C>T	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304308	NM_000280.4(PAX6):c.*3318A>G	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304311	NM_000280.4(PAX6):c.*3168C>T	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304319	NM_000280.4(PAX6):c.*2882T>C	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304324	NM_000280.4(PAX6):c.*2506C>T	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304345	NM_001368894.2(PAX6):c.*891G>A	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304350	NM_001368894.2(PAX6):c.*356T>A	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878113	NM_000280.4(PAX6):c.*3428C>T	ELP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304365	NM_001368894.2(PAX6):c.-316-8C>G	LOC106014249	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304366	NM_001368894.2(PAX6):c.-368G>A	LOC106014249	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
258168	NM_001368894.2(PAX6):c.808-12C>T	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290049	NM_001368894.2(PAX6):c.1179A>C (p.Thr393=)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304346	NM_001368894.2(PAX6):c.*841C>T	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304356	NM_001368894.2(PAX6):c.873G>A (p.Gln291=)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304357	NM_001368894.2(PAX6):c.753G>A (p.Val251=)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304362	NM_001368894.2(PAX6):c.-107C>T	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
623768	NM_001368894.2(PAX6):c.985T>C (p.Leu329=)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800413	NM_001368894.2(PAX6):c.256G>C (p.Gly86Arg)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878639	NM_001368894.2(PAX6):c.972A>T (p.Thr324=)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878640	NM_001368894.2(PAX6):c.909T>C (p.Ser303=)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAX6	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
PAX6	Orphanet:2253	Foveal hypoplasia-presenile cataract syndrome
PAX6	Orphanet:2334	Autosomal dominant keratitis
PAX6	Orphanet:250923	Isolated aniridia
PAX6	Orphanet:35737	Morning glory disc anomaly
PAX6	Orphanet:708	Peters anomaly
PAX6	Orphanet:893	WAGR syndrome
PAX6	Orphanet:98942	Coloboma of choroid and retina
PAX6	Orphanet:98943	Coloboma of eye lens
PAX6	Orphanet:98944	Coloboma of iris
PAX6	Orphanet:98945	Coloboma of macula
PAX6	Orphanet:98946	Coloboma of eyelid
PAX6	Orphanet:98947	Coloboma of optic disc

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
ELP4	HGNC:1171	ENSG00000109911	Q96EB1	Elongator complex protein 4	clinvar
PAX6	HGNC:8620	ENSG00000007372	P26367	Paired box protein Pax-6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ELP4	Elongator complex protein 4	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
PAX6	Paired box protein Pax-6	Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ELP4	Other/Unknown	no		Elongator_complex_protein_4, P-loop_NTPase
PAX6	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf

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
ventricular zone	2
calcaneal tendon	1
primordial germ cell in gonad	1
palpebral conjunctiva	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ELP4	250	ubiquitous	marker	ventricular zone, calcaneal tendon, primordial germ cell in gonad
PAX6	201	broad	marker	palpebral conjunctiva, type B pancreatic cell, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX6	4,971
ELP4	1,740

Intra-cohort edges

A	B	Sources
ELP4	PAX6	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAX6	P26367	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ELP4	Q96EB1	74.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Formation of the anterior neural plate	1	519.1×	0.006	PAX6
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	439.2×	0.006	PAX6
Regulation of gene expression in beta cells	1	259.6×	0.006	PAX6
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	259.6×	0.006	PAX6
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.025	PAX6
HATs acetylate histones	1	39.6×	0.025	ELP4

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
pancreatic A cell development	1	8426.0×	0.002	PAX6
oligodendrocyte cell fate specification	1	8426.0×	0.002	PAX6
forebrain-midbrain boundary formation	1	8426.0×	0.002	PAX6
somatic motor neuron fate commitment	1	8426.0×	0.002	PAX6
habenula development	1	2808.7×	0.004	PAX6
regulation of asymmetric cell division	1	2106.5×	0.004	PAX6
regulation of timing of cell differentiation	1	2106.5×	0.004	PAX6
ventral spinal cord interneuron specification	1	1404.3×	0.004	PAX6
commitment of neuronal cell to specific neuron type in forebrain	1	1404.3×	0.004	PAX6
salivary gland morphogenesis	1	1203.7×	0.004	PAX6
cerebral cortex regionalization	1	1203.7×	0.004	PAX6
type B pancreatic cell differentiation	1	1053.2×	0.004	PAX6
forebrain dorsal/ventral pattern formation	1	1053.2×	0.004	PAX6
lacrimal gland development	1	1053.2×	0.004	PAX6
ventral spinal cord development	1	936.2×	0.004	PAX6
positive regulation of epithelial cell differentiation	1	936.2×	0.004	PAX6
iris morphogenesis	1	936.2×	0.004	PAX6
dorsal/ventral axis specification	1	766.0×	0.004	PAX6
spinal cord motor neuron cell fate specification	1	766.0×	0.004	PAX6
cornea development in camera-type eye	1	648.1×	0.005	PAX6
tRNA wobble uridine modification	1	601.9×	0.005	ELP4
negative regulation of neuroblast proliferation	1	601.9×	0.005	PAX6
embryonic camera-type eye morphogenesis	1	561.7×	0.005	PAX6
cell fate determination	1	468.1×	0.006	PAX6
eye photoreceptor cell development	1	421.3×	0.006	PAX6
neuron fate commitment	1	401.2×	0.006	PAX6
astrocyte differentiation	1	383.0×	0.006	PAX6
signal transduction involved in regulation of gene expression	1	351.1×	0.006	PAX6
sensory organ development	1	337.0×	0.006	PAX6
pituitary gland development	1	324.1×	0.006	PAX6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
ELP4	0	0
PAX6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	ELP4, PAX6

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)
ELP4	0	—
PAX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.