Achromatopsia 4

Summary

Achromatopsia 4 (MONDO:0013465) is a disease caused by GNAT2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: GNAT2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 59

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	achromatopsia 4
Mondo ID	MONDO:0013465
MeSH	C564206
OMIM	613856
DOID	DOID:0110010
UMLS	C1841721
MedGen	330669
GARD	0015723
Is cancer (heuristic)	no

Also known as: ACHM4 · achromatopsia 4 · achromatopsia caused by mutation in GNAT2 · achromatopsia type 4 · GNAT2 achromatopsia

Data availability: 59 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › perceptual disorders › vision disorder › color vision disorder › achromatopsia › achromatopsia 4

Related subtypes (5): achromatopsia 2, achromatopsia 3, blue cone monochromacy, achromatopsia 6, achromatopsia 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

59 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 14 conflicting classifications of pathogenicity, 14 pathogenic, 4 likely pathogenic, 3 benign, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
15922	NM_001377295.2(GNAT2):c.235C>T (p.Gln79Ter)	GNAT2	Pathogenic	criteria provided, single submitter
15923	NM_001377295.2(GNAT2):c.842_843insTCAG (p.His282fs)	GNAT2	Pathogenic	no assertion criteria provided
522772	NM_001377295.2(GNAT2):c.481C>T (p.Arg161Ter)	GNAT2	Pathogenic	criteria provided, multiple submitters, no conflicts
623271	NM_001377295.2(GNAT2):c.285_291delinsCTGTAT (p.Ala96fs)	GNAT2	Pathogenic	no assertion criteria provided
623272	NM_001377295.2(GNAT2):c.303+365_461+974dup	GNAT2	Pathogenic	no assertion criteria provided
623273	NM_001377295.2(GNAT2):c.303+365_461+974del	GNAT2	Pathogenic	no assertion criteria provided
623274	NM_001377295.2(GNAT2):c.313C>T (p.Arg105Ter)	GNAT2	Pathogenic	no assertion criteria provided
623275	NM_001377295.2(GNAT2):c.503dup (p.Pro169_Ser170insTer)	GNAT2	Pathogenic	no assertion criteria provided
623276	NM_001377295.2(GNAT2):c.591-2A>C	GNAT2	Pathogenic	criteria provided, single submitter
623278	NM_001377295.2(GNAT2):c.620A>T (p.Glu207Val)	GNAT2	Pathogenic	criteria provided, single submitter
623282	NM_001377295.2(GNAT2):c.803_806dup (p.Lys270fs)	GNAT2	Pathogenic	no assertion criteria provided
623285	NM_001377295.2(GNAT2):c.937C>T (p.Arg313Ter)	GNAT2	Pathogenic	criteria provided, multiple submitters, no conflicts
623287	NM_001377295.2(GNAT2):c.955del (p.Ile319fs)	GNAT2	Pathogenic	no assertion criteria provided
812114	NM_001377295.2(GNAT2):c.605G>A (p.Gly202Glu)	GNAT2	Pathogenic	criteria provided, single submitter
3220872	NM_001377295.2(GNAT2):c.874+1G>T	GNAI3	Likely pathogenic	criteria provided, single submitter
623270	NM_001377295.2(GNAT2):c.139A>G (p.Ser47Gly)	GNAT2	Likely pathogenic	no assertion criteria provided
623277	NM_001377295.2(GNAT2):c.593T>A (p.Met198Lys)	GNAT2	Likely pathogenic	criteria provided, single submitter
623280	NM_001377295.2(GNAT2):c.720+2T>C	GNAT2	Likely pathogenic	criteria provided, single submitter
1511744	NM_001377295.2(GNAT2):c.821T>C (p.Phe274Ser)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
15925	NM_001377295.2(GNAT2):c.461+24G>A	GNAT2	Conflicting classifications of pathogenicity	no assertion criteria provided
197251	NM_001377295.2(GNAT2):c.370G>A (p.Val124Met)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198818	NM_001377295.2(GNAT2):c.933T>C (p.Asn311=)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291718	NM_001377295.2(GNAT2):c.928C>T (p.Leu310Phe)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291719	NM_001377295.2(GNAT2):c.672T>C (p.Cys224=)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291720	NM_001377295.2(GNAT2):c.609G>T (p.Gly203=)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291721	NM_001377295.2(GNAT2):c.427G>A (p.Ala143Thr)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291723	NM_001377295.2(GNAT2):c.257G>A (p.Arg86Gln)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291724	NM_001377295.2(GNAT2):c.14C>T (p.Ala5Val)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
623284	NM_001377295.2(GNAT2):c.886T>C (p.Tyr296His)	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873742	NM_001377295.2(GNAT2):c.461+10A>T	GNAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
GNAT2	Definitive	Autosomal recessive	achromatopsia 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNAT2	Orphanet:1871	Progressive cone dystrophy
GNAT2	Orphanet:49382	Achromatopsia
GNAI3	Orphanet:137888	Auriculocondylar syndrome

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
GNAT2	HGNC:4394	ENSG00000134183	P19087	Guanine nucleotide-binding protein G(t) subunit alpha-2	gencc,clinvar
GNAI3	HGNC:4387	ENSG00000065135	P08754	Guanine nucleotide-binding protein G(i) subunit alpha-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNAT2	Guanine nucleotide-binding protein G(t) subunit alpha-2	Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.
GNAI3	Guanine nucleotide-binding protein G(i) subunit alpha-3	Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.

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)
GNAT2	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
GNAI3	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert

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
oocyte	1
primordial germ cell in gonad	1
secondary oocyte	1
epithelium of esophagus	1
esophagus squamous epithelium	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNAT2	153	tissue_specific	marker	oocyte, primordial germ cell in gonad, secondary oocyte
GNAI3	289	ubiquitous	marker	esophagus squamous epithelium, epithelium of esophagus, tongue squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAI3	2,992
GNAT2	1,675

Intra-cohort edges

A	B	Sources
GNAI3	GNAT2	biogrid_interaction, intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAI3	P08754	27
GNAT2	P19087	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
G alpha (i) signalling events	2	39.0×	0.006	GNAT2, GNAI3
Adenylate cyclase inhibitory pathway	1	380.7×	0.012	GNAI3
ADP signalling through P2Y purinoceptor 12	1	248.3×	0.012	GNAI3
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.013	GNAI3
GPER1 signaling	1	124.1×	0.013	GNAI3
G alpha (z) signalling events	1	116.5×	0.013	GNAI3
Ca2+ pathway	1	89.2×	0.013	GNAT2
Extra-nuclear estrogen signaling	1	85.2×	0.013	GNAI3
G alpha (s) signalling events	1	36.6×	0.027	GNAI3

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
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	2	337.0×	2e-04	GNAT2, GNAI3
background adaptation	1	4213.0×	0.003	GNAT2
homeostasis of number of retina cells	1	2808.7×	0.003	GNAT2
neural tissue regeneration	1	2106.5×	0.003	GNAT2
cone retinal bipolar cell differentiation	1	2106.5×	0.003	GNAT2
visual behavior	1	1404.3×	0.003	GNAT2
L-glutamate import	1	1404.3×	0.003	GNAT2
reactive gliosis	1	1203.7×	0.003	GNAT2
retinal rod cell differentiation	1	936.2×	0.003	GNAT2
negative regulation of adenylate cyclase activity	1	702.2×	0.003	GNAI3
retinal cone cell development	1	702.2×	0.003	GNAT2
tissue remodeling	1	648.1×	0.003	GNAT2
GTP metabolic process	1	561.7×	0.004	GNAI3
dopamine metabolic process	1	495.6×	0.004	GNAT2
detection of light stimulus involved in visual perception	1	324.1×	0.006	GNAT2
positive regulation of macroautophagy	1	263.3×	0.006	GNAI3
phototransduction	1	247.8×	0.006	GNAT2
detection of chemical stimulus involved in sensory perception of bitter taste	1	240.7×	0.006	GNAT2
response to UV	1	183.2×	0.008	GNAT2
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	109.4×	0.012	GNAI3
cell morphogenesis	1	78.8×	0.016	GNAT2
positive regulation of cytosolic calcium ion concentration	1	58.5×	0.021	GNAT2
intracellular protein localization	1	52.3×	0.022	GNAT2
gene expression	1	39.9×	0.027	GNAT2
visual perception	1	39.8×	0.027	GNAT2
cell division	1	23.1×	0.044	GNAI3
G protein-coupled receptor signaling pathway	1	18.1×	0.054	GNAT2

Therapeutics

Drug target analysis

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

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
GNAI3	1	2
GNAT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	GNAI3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GNAI3	11	Binding:7, Functional:4

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	GNAI3

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	1	GNAI3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GNAT2

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)
GNAT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.