Is NPHS2 p.Pro175Ser (c.523C>T) pathogenic?

NPHS2 p.Pro175Ser (c.523C>T) is classified Uncertain significance in NPHS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-08-22). AlphaMissense: likely benign (0.2258); Very rare (popmax 0.00114%, sas); Associated with nephrotic syndrome, type 2.

What condition is associated with NPHS2 p.Pro175Ser (c.523C>T)?

NPHS2 p.Pro175Ser (c.523C>T) is associated with nephrotic syndrome, type 2 (ClinVar).

How common is NPHS2 p.Pro175Ser (c.523C>T) in the general population?

NPHS2 p.Pro175Ser (c.523C>T) is very rare (popmax 0.00114%, sas) (gnomAD).

What do computational predictors say about NPHS2 p.Pro175Ser (c.523C>T)?

AlphaMissense predicts likely benign (score 0.2258) — an in-silico prediction, not a clinical call.

NPHS2 p.Pro175Ser

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.523C>T · rs1472510122 · VCV553500

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00114%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 2

Computational evidence

Protein change
AlphaMissense	0.2258	likely benign
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -9.19	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 25 kb · p 0.063 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00114% South Asian · 1/87,360 alleles

Overall 6.31e-05% 1/1,585,240 alleles · very rare exomes 1/1,433,002 · genomes 0/152,238 · joint denominator

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.Pro175Ser
Coding: c.523C>T
MANE Select: NM_014625
dbSNP: rs1472510122
Type: single nucleotide variant
Location: chr1:179559690 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.00
Residue 175: a UniProt-annotated variant site (in nphs2); a UniProt-annotated variant site (in nphs2; requires 2 nucleotide substitutions)

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.Pro175Thr Uncertain significance ★★ ⚠ same residue
NPHS2 p.Pro175His Uncertain significance ★ ⚠ same residue
NPHS2 p.Pro175Leu Uncertain significance ★ ⚠ 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

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-pro175ser (accessed [today's date]).

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