Cataract 9 multiple types

Summary

Cataract 9 multiple types (MONDO:0011413) is a disease caused by CRYAA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CRYAA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 74

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract 9 multiple types
Mondo ID	MONDO:0011413
OMIM	604219
DOID	DOID:0110266
UMLS	C1858679
MedGen	347693
GARD	0015364
Is cancer (heuristic)	no

Also known as: cataract (disease) caused by mutation in CRYAA · cataract 9, multiple types · CRYAA cataract (disease) · CTRCT9

Data availability: 74 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › lens disorder › cataract › cataract 9 multiple types

Related subtypes (28): immature cataract, diabetic cataract, mature cataract, tetanic cataract, myotonic cataract, senile cataract, diabetes mellitus type 2 associated cataract, cataract 4 multiple types, cataract 29, cataract 1 multiple types, early-onset non-syndromic cataract, cataract 3 multiple types, cataract 28, cataract 18, cataract 12 multiple types, cataract 34 multiple types, cataract 36, bhaskar jagannathan syndrome, autosomal dominant cataract, craniostenosis cataract, Kozlowski Rafinski Klicharska syndrome, cataract 49, cataract 48, hypermature cataract, nuclear cataract, cortical cataract, cataract 2, multiple types, cataract 50 with or without glaucoma

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

74 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 18 likely benign, 9 benign, 5 pathogenic, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16957	NM_000394.4(CRYAA):c.346C>T (p.Arg116Cys)	CRYAA	Pathogenic	criteria provided, multiple submitters, no conflicts
16960	NM_000394.4(CRYAA):c.347G>A (p.Arg116His)	CRYAA	Pathogenic	criteria provided, multiple submitters, no conflicts
68456	NM_000394.4(CRYAA):c.292G>A (p.Gly98Arg)	CRYAA	Pathogenic	criteria provided, multiple submitters, no conflicts
68457	NM_000394.4(CRYAA):c.160C>T (p.Arg54Cys)	CRYAA	Pathogenic	criteria provided, multiple submitters, no conflicts
68459	NM_000394.4(CRYAA):c.34C>T (p.Arg12Cys)	CRYAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68460	NM_000394.4(CRYAA):c.61C>T (p.Arg21Trp)	CRYAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68461	NM_000394.4(CRYAA):c.62G>A (p.Arg21Gln)	CRYAA	Pathogenic	criteria provided, multiple submitters, no conflicts
3731277	NM_000394.4(CRYAA):c.347G>T (p.Arg116Leu)	CRYAA	Likely pathogenic	criteria provided, single submitter
16959	NM_000394.4(CRYAA):c.145C>T (p.Arg49Cys)	CRYAA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252948	NM_000394.4(CRYAA):c.440del (p.Gln147fs)	CRYAA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2574040	NM_000394.4(CRYAA):c.161G>C (p.Arg54Pro)	CRYAA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340096	NM_000394.4(CRYAA):c.154C>T (p.Leu52Phe)	CRYAA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1345527	NM_000394.4(CRYAA):c.322_327dup (p.Gly108_Tyr109dup)	CRYAA	Uncertain significance	criteria provided, single submitter
1366904	NM_000394.4(CRYAA):c.508G>A (p.Ala170Thr)	CRYAA	Uncertain significance	criteria provided, single submitter
1372044	NM_000394.4(CRYAA):c.35G>A (p.Arg12His)	CRYAA	Uncertain significance	criteria provided, single submitter
1482119	NM_000394.4(CRYAA):c.75G>C (p.Gln25His)	CRYAA	Uncertain significance	criteria provided, single submitter
2195346	NM_000394.4(CRYAA):c.506C>T (p.Ser169Leu)	CRYAA	Uncertain significance	criteria provided, single submitter
2210771	NM_000394.4(CRYAA):c.166G>A (p.Val56Met)	CRYAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
2363101	NM_000394.4(CRYAA):c.514T>C (p.Ser172Pro)	CRYAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
2514624	NM_000394.4(CRYAA):c.50T>C (p.Phe17Ser)	CRYAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
2985948	NM_000394.4(CRYAA):c.190-24_190-10del	CRYAA	Uncertain significance	criteria provided, single submitter
340097	NM_000394.4(CRYAA):c.245C>T (p.Pro82Leu)	CRYAA	Uncertain significance	criteria provided, single submitter
340099	NM_000394.4(CRYAA):c.269A>C (p.Gln90Pro)	CRYAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
340101	NM_000394.4(CRYAA):c.375C>A (p.Asp125Glu)	CRYAA	Uncertain significance	criteria provided, single submitter
340102	NM_000394.4(CRYAA):c.464C>A (p.Ala155Asp)	CRYAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
340103	NM_000394.4(CRYAA):c.488G>A (p.Arg163Gln)	CRYAA	Uncertain significance	criteria provided, single submitter
340107	NM_000394.4(CRYAA):c.*193G>A	CRYAA	Uncertain significance	criteria provided, single submitter
340108	NM_000394.4(CRYAA):c.*253C>T	CRYAA	Uncertain significance	criteria provided, single submitter
340109	NM_000394.4(CRYAA):c.*333G>A	CRYAA	Uncertain significance	criteria provided, single submitter
340110	NM_000394.4(CRYAA):c.*376G>C	CRYAA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
CRYAA	Definitive	Autosomal recessive	cataract 9 multiple types	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRYAA	Orphanet:1377	Cataract-microcornea syndrome
CRYAA	Orphanet:441452	Early-onset lamellar cataract
CRYAA	Orphanet:98988	Early-onset anterior polar cataract
CRYAA	Orphanet:98991	Early-onset nuclear cataract
CRYAA	Orphanet:98994	Total early-onset cataract

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
CRYAA	HGNC:2388	ENSG00000160202	P02489	Alpha-crystallin A chain	gencc,clinvar
KRTAP12-2	HGNC:20530	ENSG00000221864	P59991	Keratin-associated protein 12-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRYAA	Alpha-crystallin A chain	Contributes to the transparency and refractive index of the lens.
KRTAP12-2	Keratin-associated protein 12-2	In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through t…

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)
CRYAA	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
KRTAP12-2	Other/Unknown	no		KRTAP_PMG

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	1
liver	1
right lobe of liver	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRYAA	42		marker	adult mammalian kidney, right lobe of liver, liver
KRTAP12-2	16		yes	male germ line stem cell (sensu Vertebrata) in testis, sural nerve, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYAA	1,464
KRTAP12-2	773

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRYAA	P02489	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRTAP12-2	P59991	70.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Keratinization	1	55.7×	0.036	KRTAP12-2
Developmental Biology	1	14.5×	0.069	KRTAP12-2

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
negative regulation of intracellular transport	1	5617.3×	0.002	CRYAA
response to UV-A	1	4213.0×	0.002	CRYAA
apoptotic process involved in morphogenesis	1	2808.7×	0.002	CRYAA
lens fiber cell morphogenesis	1	2106.5×	0.002	CRYAA
tubulin complex assembly	1	1685.2×	0.002	CRYAA
glutathione biosynthetic process	1	1532.0×	0.002	CRYAA
embryonic camera-type eye morphogenesis	1	1123.5×	0.003	CRYAA
microtubule-based process	1	991.3×	0.003	CRYAA
protein refolding	1	624.1×	0.004	CRYAA
response to hydrogen peroxide	1	468.1×	0.004	CRYAA
response to heat	1	421.3×	0.004	CRYAA
lens development in camera-type eye	1	374.5×	0.004	CRYAA
positive regulation of cell growth	1	183.2×	0.008	CRYAA
mitochondrion organization	1	151.8×	0.009	CRYAA
actin filament organization	1	118.7×	0.011	CRYAA
response to hypoxia	1	95.8×	0.013	CRYAA
visual perception	1	79.5×	0.015	CRYAA
negative regulation of gene expression	1	69.1×	0.016	CRYAA
protein stabilization	1	66.9×	0.016	CRYAA
negative regulation of apoptotic process	1	34.8×	0.029	CRYAA

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
CRYAA	0	0
KRTAP12-2	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
CRYAA	25	Binding:25

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	CRYAA, KRTAP12-2

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)
CRYAA	25	—
KRTAP12-2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.