Is PTPRO p.Val809Ile (c.2425G>A) pathogenic?

PTPRO p.Val809Ile (c.2425G>A) is classified Uncertain significance in PTPRO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.071); Ultra-rare (popmax 0.0126%, afr); Associated with nephrotic syndrome, type 6.

What condition is associated with PTPRO p.Val809Ile (c.2425G>A)?

PTPRO p.Val809Ile (c.2425G>A) is associated with nephrotic syndrome, type 6 (ClinVar).

How common is PTPRO p.Val809Ile (c.2425G>A) in the general population?

PTPRO p.Val809Ile (c.2425G>A) is ultra-rare (popmax 0.0126%, afr) (gnomAD).

What do computational predictors say about PTPRO p.Val809Ile (c.2425G>A)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

PTPRO p.Val809Ile

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.2425G>A · VCV3574494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 6

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP -0.61, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 258 kb · p 0.015 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0126% African / African-American · 9/71,220 alleles

Filtering AF 0.00653% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00489%

Overall 0.00299% 48/1,605,982 alleles · ultra-rare exomes 40/1,457,396 · genomes 8/148,586 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0126%	7,913
East Asian	0.00894%	11,187
Admixed American	0.00503%	19,865
South Asian	0.00444%	22,497
Remaining individualsnot grpmax-eligible	0.00322%	31,104
European (non-Finnish)	0.00221%	45,308

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.Val809Ile
Coding: c.2425G>A
MANE Select: NM_030667
Type: single nucleotide variant
Location: chr12:15549214 (GRCh38)
Gene constraint: LOEUF 0.513 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 2 PDB
Residue 809: the fibronectin type-iii 8 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.Val809Asp Uncertain significance ★ ⚠ same residue
PTPRO p.Val809= Likely benign ★ same residue
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

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-val809ile (accessed [today's date]).

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