NPHS2

Chr 1AR

NPHS2 stomatin family member, podocin

Also known as: PDCN, SRN1

NCBI Gene: 7827 ENSG00000116218 UniProt: Q9NP85 OMIM: 604766

The protein encoded by this gene regulates glomerular permeability by linking the plasma membrane to the cytoskeleton in kidney podocytes. Mutations cause autosomal recessive steroid-resistant nephrotic syndrome, typically presenting in early childhood. The gene is highly intolerant to loss-of-function variants, reflecting its critical role in maintaining the kidney filtration barrier.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Nephrotic syndrome, type 2MIM #600995

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Nephrotic syndrome, type 2; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.18

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — NPHS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 0.97

OE 0.76 (0.51–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.69Z-score

OE missense 0.86 (0.76–0.98)

174 obs / 201.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.51–1.18)

0≤0.351.4

Missense OE?0.86 (0.76–0.98)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 19.7Missense obs/exp: 174 / 201.4Syn Z: -0.08

Background carrier burden — how many people carry a rare variant somewhere in NPHS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

474 rare PASS variants

Rare truncating (LoF)

1 in 1,100

93 rare PASS variants

Rare synonymous (reference)

1 in 270

209 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NPHS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 1,100
South Asian	~43k	1 in 130	1 in 1,000
Remaining (unassigned)	~30k	1 in 97	1 in 1,100
European (Finnish)	~27k	1 in 220	1 in 1,500
Admixed American	~22k	1 in 96	1 in 760
African / African American	~21k	1 in 140	1 in 1,400
East Asian	~20k	1 in 110	1 in 1,800
Ashkenazi Jewish	~13k	1 in 790	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓