Is NPHS2 p.Ser46= (c.138G>A) pathogenic?

NPHS2 p.Ser46= (c.138G>A) is classified Conflicting classifications of pathogenicity in NPHS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-11). Very rare (popmax 0.00244%, eas); Associated with nephrotic syndrome, type 2.

What condition is associated with NPHS2 p.Ser46= (c.138G>A)?

NPHS2 p.Ser46= (c.138G>A) is associated with nephrotic syndrome, type 2 (ClinVar).

How common is NPHS2 p.Ser46= (c.138G>A) in the general population?

NPHS2 p.Ser46= (c.138G>A) is very rare (popmax 0.00244%, eas) (gnomAD).

NPHS2 p.Ser46=

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.138G>A · rs1053139144 · VCV1086502

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Conditions

nephrotic syndrome, type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.4
Overall
CADD	2.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00244% East Asian · 1/40,922 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000585% 9/1,539,618 alleles · very rare exomes 8/1,387,564 · genomes 1/152,054 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00835%	11,979
East Asiangrpmax	0.00244%	40,922
Admixed American	0.00196%	51,088
European (non-Finnish)	0.000174%	573,766

Remaining individuals 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.Ser46=
Coding: c.138G>A
MANE Select: NM_014625
dbSNP: rs1053139144
Type: single nucleotide variant
Location: chr1:179575727 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.00
Residue 46: a UniProt-annotated variant site (in nphs2); the 'disordered' region

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

For Hereditary steroid-resistant nephrotic syndrome (Orphanet):

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

Similar variants

NPHS2 p.Ser46fs Likely pathogenic ★★ same residue
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+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-ser46 (accessed [today's date]).

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