Is PTPRO p.Phe526= (c.1578T>C) pathogenic?

PTPRO p.Phe526= (c.1578T>C) is classified Conflicting classifications of pathogenicity in PTPRO (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-13). Ultra-rare (popmax 0.045%, sas); Associated with nephrotic syndrome, type 6.

What condition is associated with PTPRO p.Phe526= (c.1578T>C)?

PTPRO p.Phe526= (c.1578T>C) is associated with nephrotic syndrome, type 6 (ClinVar).

How common is PTPRO p.Phe526= (c.1578T>C) in the general population?

PTPRO p.Phe526= (c.1578T>C) is ultra-rare (popmax 0.045%, sas) (gnomAD).

PTPRO p.Phe526=

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.1578T>C · rs755074605 · VCV2048493

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, sas)

Conditions

nephrotic syndrome, type 6

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 0.41	phastCons 1
Overall
CADD	6.601	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.045% South Asian · 41/91,084 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00756% 122/1,613,934 alleles · ultra-rare exomes 118/1,461,792 · genomes 4/152,142 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.045%	2,222
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00636%	15,733

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: PTPRO
Protein: p.Phe526=
Coding: c.1578T>C
MANE Select: NM_030667
dbSNP: rs755074605
Type: single nucleotide variant
Location: chr12:15515611 (GRCh38)
Gene constraint: LOEUF 0.513 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 2 PDB
Residue 526: the fibronectin type-iii 5 domain

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

Disease context

nephrotic syndrome, type 6 — 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

PTPRO p.Ala1086Val Uncertain significance ★★ ⚠ same condition
PTPRO p.Ala591Thr Uncertain significance ★★ ⚠ same condition
PTPRO p.Arg480Trp Uncertain significance ★★ same condition
PTPRO p.Arg607Gln Uncertain significance ★★ ⚠ same condition
PTPRO p.Asp162Val Uncertain significance ★★ ⚠ same condition
PTPRO p.Asp799Gly Uncertain significance ★★ ⚠ same condition
PTPRO p.Glu214Lys Uncertain significance ★★ ⚠ same condition
PTPRO p.Glu564Lys Uncertain significance ★★ ⚠ 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/ptpro-p-phe526 (accessed [today's date]).

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