Isolated microphthalmia 6

Summary

Isolated microphthalmia 6 (MONDO:0013293) is a disease caused by PRSS56 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PRSS56 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 112

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated microphthalmia 6
Mondo ID	MONDO:0013293
OMIM	613517
DOID	DOID:0060835
UMLS	C3150757
MedGen	462107
GARD	0018628
Is cancer (heuristic)	no

Also known as: isolated microphthalmia caused by mutation in PRSS56 · isolated microphthalmia type 6 · MCOP6 · microphthalmia, isolated 6 · microphthalmia, isolated type 6 · PRSS56 isolated microphthalmia · PRSS56-related nanophthalmos

Data availability: 112 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 › isolated microphthalmia › isolated microphthalmia 6

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 7, isolated microphthalmia 8

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

112 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 27 likely benign, 22 benign, 16 pathogenic, 7 likely pathogenic, 3 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2628024	NM_018942.3(HMX1):c.691_692dup (p.Glu232fs)	HMX1	Pathogenic	criteria provided, single submitter
1324965	NM_001195129.2(PRSS56):c.1066del (p.Gln356fs)	PRSS56	Pathogenic	criteria provided, multiple submitters, no conflicts
1333280	NM_001195129.2(PRSS56):c.219del (p.Arg74fs)	PRSS56	Pathogenic	criteria provided, single submitter
1385526	NM_001195129.2(PRSS56):c.353G>A (p.Trp118Ter)	PRSS56	Pathogenic	criteria provided, single submitter
1450154	NM_001195129.2(PRSS56):c.1573del (p.Val525fs)	PRSS56	Pathogenic	criteria provided, single submitter
183172	NM_001195129.2(PRSS56):c.833dup (p.Val279fs)	PRSS56	Pathogenic	no assertion criteria provided
183173	NM_001195129.2(PRSS56):c.709G>A (p.Gly237Arg)	PRSS56	Pathogenic	no assertion criteria provided
183174	NM_001195129.2(PRSS56):c.1183T>C (p.Cys395Arg)	PRSS56	Pathogenic	no assertion criteria provided
2047480	NM_001195129.2(PRSS56):c.1258G>T (p.Gly420Ter)	PRSS56	Pathogenic	criteria provided, single submitter
2855573	NM_001195129.2(PRSS56):c.896dup (p.Pro299_Arg300insTer)	PRSS56	Pathogenic	criteria provided, single submitter
31077	NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs)	PRSS56	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31079	NM_001195129.2(PRSS56):c.926G>C (p.Trp309Ser)	PRSS56	Pathogenic	no assertion criteria provided
31080	NM_001195129.2(PRSS56):c.526C>G (p.Arg176Gly)	PRSS56	Pathogenic	no assertion criteria provided
3631009	NM_001195129.2(PRSS56):c.849+1G>T	PRSS56	Pathogenic	criteria provided, single submitter
3641485	NM_001195129.2(PRSS56):c.849+1G>C	PRSS56	Pathogenic	criteria provided, single submitter
4750585	NM_001195129.2(PRSS56):c.649del (p.Gln217fs)	PRSS56	Pathogenic	criteria provided, single submitter
915448	NM_001195129.2(PRSS56):c.1202C>A (p.Ala401Glu)	PRSS56	Pathogenic	no assertion criteria provided
183170	NM_001195129.2(PRSS56):c.958G>A (p.Gly320Arg)	PRSS56	Likely pathogenic	criteria provided, single submitter
183175	NM_001195129.2(PRSS56):c.1555G>A (p.Gly519Arg)	PRSS56	Likely pathogenic	criteria provided, single submitter
4277282	NM_001195129.2(PRSS56):c.320G>T (p.Gly107Val)	PRSS56	Likely pathogenic	criteria provided, single submitter
4277283	NM_001195129.2(PRSS56):c.632G>C (p.Cys211Ser)	PRSS56	Likely pathogenic	criteria provided, single submitter
4277285	NM_001195129.2(PRSS56):c.1186G>A (p.Glu396Lys)	PRSS56	Likely pathogenic	criteria provided, single submitter
4686564	NM_001195129.2(PRSS56):c.970C>T (p.Arg324Cys)	PRSS56	Likely pathogenic	criteria provided, single submitter
932138	NM_001195129.2(PRSS56):c.94del (p.Gln32fs)	PRSS56	Likely pathogenic	criteria provided, single submitter
1304588	NM_001195129.2(PRSS56):c.292G>A (p.Val98Met)	PRSS56	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1569529	NM_001195129.2(PRSS56):c.1262T>G (p.Leu421Arg)	PRSS56	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2591134	NM_001195129.2(PRSS56):c.517C>G (p.Pro173Ala)	PRSS56	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055451	NM_001195129.2(PRSS56):c.1463G>A (p.Gly488Glu)	PRSS56	Uncertain significance	criteria provided, single submitter
1057381	NM_001195129.2(PRSS56):c.1631C>T (p.Pro544Leu)	PRSS56	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333396	NM_001195129.2(PRSS56):c.1222C>G (p.Leu408Val)	PRSS56	Uncertain significance	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
PRSS56	Definitive	Autosomal recessive	isolated microphthalmia 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRSS56	Orphanet:35612	Nanophthalmos
HMX1	Orphanet:157962	Oculoauricular syndrome, Schorderet type

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
PRSS56	HGNC:39433	ENSG00000237412	P0CW18	Serine protease 56	gencc,clinvar
HMX1	HGNC:5017	ENSG00000215612	Q9NP08	Homeobox protein HMX1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRSS56	Serine protease 56	Serine protease required during eye development.
HMX1	Homeobox protein HMX1	DNA-binding protein that binds to the 5’-CAAG-3’ core sequence.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Protease	1	18.3×	0.108
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRSS56	Protease	yes		Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
HMX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
amygdala	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRSS56	47	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, muscle of leg
HMX1	43	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, amygdala

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRSS56	766
HMX1	217

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRSS56	P0CW18	74.35
HMX1	Q9NP08	63.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
camera-type eye development	1	179.3×	0.028	PRSS56
blood coagulation	1	86.9×	0.029	PRSS56
proteolysis	1	17.1×	0.078	PRSS56
negative regulation of DNA-templated transcription	1	15.8×	0.078	HMX1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	HMX1

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
PRSS56	0	0
HMX1	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	1	PRSS56
E	Difficult family or no structure, no drug	1	HMX1

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)
PRSS56	0	—
HMX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.