Is NPHS2 p.Ser96= (c.288C>T) pathogenic?

NPHS2 p.Ser96= (c.288C>T) is classified Benign/Likely benign in NPHS2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 9.05%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with nephrotic syndrome, type 2.

What condition is associated with NPHS2 p.Ser96= (c.288C>T)?

NPHS2 p.Ser96= (c.288C>T) is associated with nephrotic syndrome, type 2, steroid-resistant nephrotic syndrome (ClinVar).

NPHS2 p.Ser96=

Q: How common is NPHS2 p.Ser96= (c.288C>T) in the general population?

NPHS2 p.Ser96= (c.288C>T) is common (popmax 9.05%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Hereditary steroid-resistant nephrotic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.288C>T · rs3738423 · VCV260426

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 9.05%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

nephrotic syndrome, type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.21	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -0.32	GERP -2.8
Overall
CADD	3.262	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.05% European (non-Finnish) · 106,612/1,178,576 alleles

Filtering AF 9% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.98%

Overall 8.42% 135,724/1,612,474 alleles · common exomes 122,921/1,460,280 · genomes 12,803/152,194 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	13.1%	8
Amishnot grpmax-eligible	11.2%	9
European (non-Finnish)grpmax	9.05%	11
African / African-American	8.65%	12
Remaining individualsnot grpmax-eligible	8.24%	12
East Asian	7%	14
Ashkenazi Jewishnot grpmax-eligible	6.56%	15
Admixed American	4.31%	23
Middle Eastern	1.4%	71
South Asian	1.37%	73

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPHS2
Protein: p.Ser96=
Coding: c.288C>T
MANE Select: NM_014625
dbSNP: rs3738423
Type: single nucleotide variant
Location: chr1:179564780 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.00
Residue 96: a UniProt-annotated variant site (in nphs2)

Full NPHS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrotic syndrome, type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: steroid-resistant nephrotic syndrome

For Hereditary steroid-resistant nephrotic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal

Similar variants

NPHS2 c.275-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHS2 c.378+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHS2 c.451+2T>A Likely pathogenic ★★ same condition
NPHS2 c.451+3A>T Pathogenic/Likely pathogenic ★★ same condition
NPHS2 c.535-1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHS2 c.738+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHS2 c.738+1G>C Pathogenic ★★ same condition
NPHS2 c.738+2T>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nphs2-p-ser96 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown