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…

LOFmechanismARLOEUF 1.182 OMIM phenotypes

Clinical Summary— NPHS2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

166 unique Pathogenic / Likely Pathogenic· 160 VUS of 628 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNPHS2-related nephrotic syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.6247th %ile

LOF

0.3550th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

628 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46

Likely Pathogenic120

VUS160

Likely Benign235

Benign32

Conflicting33

Pathogenic

120

Likely Pathogenic

160

VUS

235

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	7	5	0	46
Likely Pathogenic	83	35	2	0	120
VUS	2	131	19	8	160
Likely Benign	1	4	80	150	235
Benign	0	0	30	2	32
Conflicting	—				33
Total	120	177	136	160	626

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

28 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap NPHS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →