Is NPHS1 p.Pro73= (c.219C>T) pathogenic?

NPHS1 p.Pro73= (c.219C>T) is classified Likely benign in NPHS1 (ClinVar, Single submitter, 3 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0415%, nfe); Associated with congenital nephrotic syndrome, Finnish type.

What condition is associated with NPHS1 p.Pro73= (c.219C>T)?

NPHS1 p.Pro73= (c.219C>T) is associated with congenital nephrotic syndrome, Finnish type (ClinVar).

How common is NPHS1 p.Pro73= (c.219C>T) in the general population?

NPHS1 p.Pro73= (c.219C>T) is ultra-rare (popmax 0.0415%, nfe) (gnomAD).

How is Congenital nephrotic syndrome, Finnish type inherited?

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

NPHS1 p.Pro73=

c.219C>T · rs115599462 · VCV727772

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0415%, nfe)

Conditions

congenital nephrotic syndrome, Finnish type

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 -9.9	GERP -4.1
Overall
CADD	1.627	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0415% European (non-Finnish) · 490/1,179,988 alleles

Filtering AF 0.0385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0372%

Overall 0.0334% 539/1,613,654 alleles · ultra-rare exomes 500/1,461,412 · genomes 39/152,242 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0415%	2,408
Finnishnot grpmax-eligible	0.0346%	2,892
Remaining individualsnot grpmax-eligible	0.0208%	4,806
Admixed American	0.01%	10,004
African / African-American	0.008%	12,504
East Asian	0.00223%	44,868
South Asian	0.0011%	91,064

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.Pro73=
Coding: c.219C>T
MANE Select: NM_004646
dbSNP: rs115599462
Type: single nucleotide variant
Location: chr19:35851512 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.23 · 1 PDB
Residue 73: the ig-like c2-type 1 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 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
NPHS1 c.2663+2T>A 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-pro73 (accessed [today's date]).

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