pseudohypoaldosteronism type 2D

Summary

pseudohypoaldosteronism type 2D (MONDO:0013781) is a disease caused by KLHL3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KLHL3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 207

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoaldosteronism type 2D
Mondo ID	MONDO:0013781
OMIM	614495
Orphanet	300525
ICD-11	1679339588
UMLS	C3469605
MedGen	483335
GARD	0017372
Is cancer (heuristic)	no

Also known as: KLHL3 pseudohypoaldosteronism type 2 · PHA2D · pseudohypoaldosteronism type 2 caused by mutation in KLHL3 · pseudohypoaldosteronism, type IID

Data availability: 207 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubular transport disease › pseudohypoaldosteronism › inherited pseudohypoaldosteronism › pseudohypoaldosteronism type 2 › pseudohypoaldosteronism type 2D

Related subtypes (4): pseudohypoaldosteronism type 2A, pseudohypoaldosteronism type 2B, pseudohypoaldosteronism type 2C, pseudohypoaldosteronism type 2E

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

207 retrieved; paginated sample, class counts are floors:

140 uncertain significance, 38 benign, 9 pathogenic, 5 likely pathogenic, 5 benign/likely benign, 5 likely benign, 3 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100527	NM_017415.3(KLHL3):c.1410G>A (p.Trp470Ter)	KLHL3	Pathogenic	no assertion criteria provided
30516	NM_017415.3(KLHL3):c.965T>G (p.Phe322Cys)	KLHL3	Pathogenic	no assertion criteria provided
30517	NM_017415.3(KLHL3):c.1229C>T (p.Ser410Leu)	KLHL3	Pathogenic	no assertion criteria provided
30518	NM_017415.3(KLHL3):c.1583G>A (p.Arg528His)	KLHL3	Pathogenic	criteria provided, multiple submitters, no conflicts
30519	NM_017415.3(KLHL3):c.718C>T (p.Arg240Ter)	KLHL3	Pathogenic	criteria provided, multiple submitters, no conflicts
30520	NM_017415.3(KLHL3):c.1007G>T (p.Arg336Ile)	KLHL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30523	NM_017415.3(KLHL3):c.1298G>A (p.Ser433Asn)	KLHL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31544	NM_017415.3(KLHL3):c.1193C>T (p.Ala398Val)	KLHL3	Pathogenic	no assertion criteria provided
31545	NM_017415.3(KLHL3):c.1587C>A (p.Asn529Lys)	KLHL3	Pathogenic	no assertion criteria provided
31546	NM_017415.3(KLHL3):c.1277C>T (p.Pro426Leu)	KLHL3	Pathogenic	no assertion criteria provided
3235152	NM_017415.3(KLHL3):c.1554_1570dup (p.Asn524delinsSerLysTrpGlnThrTer)	KLHL3	Pathogenic	criteria provided, single submitter
100537	NM_017415.3(KLHL3):c.1280T>C (p.Met427Thr)	KLHL3	Likely pathogenic	criteria provided, single submitter
100550	NM_017415.3(KLHL3):c.1295G>A (p.Ser432Asn)	KLHL3	Likely pathogenic	criteria provided, single submitter
1177423	NM_017415.3(KLHL3):c.1000C>T (p.Pro334Ser)	KLHL3	Likely pathogenic	criteria provided, single submitter
30522	NM_017415.3(KLHL3):c.1582C>T (p.Arg528Cys)	KLHL3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3591715	NM_017415.3(KLHL3):c.1291C>T (p.Arg431Trp)	KLHL3	Likely pathogenic	criteria provided, single submitter
350989	NM_017415.3(KLHL3):c.1021+5G>A	KLHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
350993	NM_017415.3(KLHL3):c.756G>A (p.Thr252=)	KLHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3591746	NM_017415.3(KLHL3):c.234G>A (p.Met78Ile)	KLHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
100530	NM_017415.3(KLHL3):c.1019C>T (p.Ala340Val)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
100536	NM_017415.3(KLHL3):c.1160T>C (p.Leu387Pro)	KLHL3	Uncertain significance	criteria provided, single submitter
1314383	NM_017415.3(KLHL3):c.1654G>T (p.Ala552Ser)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1986389	NM_017415.3(KLHL3):c.467G>A (p.Arg156His)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2176270	NM_017415.3(KLHL3):c.173A>G (p.Asp58Gly)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
217888	NM_017415.3(KLHL3):c.1519G>A (p.Val507Ile)	KLHL3	Uncertain significance	criteria provided, single submitter
2183588	NM_017415.3(KLHL3):c.738G>T (p.Arg246Ser)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2184396	NM_017415.3(KLHL3):c.526+5G>T	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2299376	NM_017415.3(KLHL3):c.796A>G (p.Lys266Glu)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2337130	NM_017415.3(KLHL3):c.365T>C (p.Val122Ala)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2383861	NM_017415.3(KLHL3):c.74C>T (p.Thr25Met)	KLHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
KLHL3	Strong	Autosomal dominant	pseudohypoaldosteronism type 2D	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KLHL3	Orphanet:300525	Pseudohypoaldosteronism type 2D

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KLHL3	HGNC:6354	ENSG00000146021	Q9UH77	Kelch-like protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLHL3	Kelch-like protein 3	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KLHL3	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

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)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar vermis	1
cerebellum	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLHL3	262	broad	marker	cerebellar vermis, middle temporal gyrus, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLHL3	947

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLHL3	Q9UH77	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
Class I MHC mediated antigen processing & presentation	1	70.1×	0.059	KLHL3
Neddylation	1	47.4×	0.059	KLHL3
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.059	KLHL3
Adaptive Immune System	1	29.8×	0.059	KLHL3
Post-translational protein modification	1	19.2×	0.073	KLHL3
Immune System	1	13.0×	0.081	KLHL3
Metabolism of proteins	1	12.4×	0.081	KLHL3

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
distal tubule morphogenesis	1	8426.0×	0.001	KLHL3
monoatomic ion homeostasis	1	2407.4×	0.002	KLHL3
renal sodium ion absorption	1	991.3×	0.003	KLHL3
potassium ion homeostasis	1	766.0×	0.003	KLHL3
macroautophagy	1	240.7×	0.008	KLHL3
protein K48-linked ubiquitination	1	168.5×	0.010	KLHL3
gene expression	1	79.9×	0.017	KLHL3
ubiquitin-dependent protein catabolic process	1	74.2×	0.017	KLHL3
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.021	KLHL3
protein ubiquitination	1	41.4×	0.024	KLHL3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KLHL3	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
KLHL3	3	Binding:3

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KLHL3

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)
KLHL3	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.