Is NPHS1 p.Pro519Ser (c.1555C>T) pathogenic?

NPHS1 p.Pro519Ser (c.1555C>T) is classified Likely pathogenic in NPHS1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.328); Very rare (popmax 0.0023%, nfe); Associated with congenital nephrotic syndrome, Finnish type.

What condition is associated with NPHS1 p.Pro519Ser (c.1555C>T)?

NPHS1 p.Pro519Ser (c.1555C>T) is associated with congenital nephrotic syndrome, Finnish type (ClinVar).

How common is NPHS1 p.Pro519Ser (c.1555C>T) in the general population?

NPHS1 p.Pro519Ser (c.1555C>T) is very rare (popmax 0.0023%, nfe) (gnomAD).

How is Congenital nephrotic syndrome, Finnish type inherited?

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

What do computational predictors say about NPHS1 p.Pro519Ser (c.1555C>T)?

AlphaMissense predicts likely benign (score 0.328) — an in-silico prediction, not a clinical call.

NPHS1 p.Pro519Ser

c.1555C>T · rs386833884 · VCV56442

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital nephrotic syndrome, Finnish type

Computational evidence

Protein change
AlphaMissense	0.328	likely benign ⚠ discordant with ClinVar
REVEL	0.481	indeterminate
SaProt	LLR -10.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 25 kb · p 0.068 · regional, not allelic
Overall
CADD	28.4	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 0.0023% European (non-Finnish) · 27/1,171,804 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00175% 28/1,596,152 alleles · very rare exomes 26/1,443,982 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0023%	43,400
Admixed American	0.00174%	57,390

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: NPHS1
Protein: p.Pro519Ser
Coding: c.1555C>T
MANE Select: NM_004646
dbSNP: rs386833884
Type: single nucleotide variant
Location: chr19:35846080 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.23 · 1 PDB
Residue 519: a UniProt-annotated variant site (in nphs1); the ig-like c2-type 5 domain

Full NPHS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Congenital nephrotic syndrome, Finnish type (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

NPHS1 p.Pro519= Likely benign ★ same residue
NPHS1 c.1012+2T>A Likely pathogenic ★★ same condition
NPHS1 c.1315+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHS1 c.1440+1G>A Pathogenic ★★ same condition
NPHS1 c.1930+5G>A Likely pathogenic ★★ same condition
NPHS1 c.2071+2T>C Pathogenic/Likely pathogenic ★★ same condition
NPHS1 c.2335-1G>A Pathogenic ★★ same condition
NPHS1 c.2506+1G>A 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/nphs1-p-pro519ser (accessed [today's date]).

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