Is PTPRO p.Val593Met (c.1777G>A) pathogenic?

PTPRO p.Val593Met (c.1777G>A) is classified Conflicting classifications of pathogenicity in PTPRO (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.2469); Rare (popmax 0.348%, sas).

How common is PTPRO p.Val593Met (c.1777G>A) in the general population?

PTPRO p.Val593Met (c.1777G>A) is rare (popmax 0.348%, sas) (gnomAD).

What do computational predictors say about PTPRO p.Val593Met (c.1777G>A)?

AlphaMissense predicts likely benign (score 0.2469) — an in-silico prediction, not a clinical call.

PTPRO p.Val593Met

c.1777G>A · rs368334371 · VCV2159946

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2469 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.348%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2469	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -8.04	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 8.2	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 258 kb · p 0.015 · regional, not allelic
Overall
CADD	26.2	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 0.348% South Asian · 317/91,042 alleles

Filtering AF 0.317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.304%

Overall 0.0221% 357/1,611,910 alleles · rare exomes 325/1,459,604 · genomes 32/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.348%	287
Middle Eastern	0.132%	758
Remaining individualsnot grpmax-eligible	0.0256%	3,902
East Asian	0.00223%	44,874
Admixed American	0.00167%	60,018
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.0011%	90,613

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.Val593Met
Coding: c.1777G>A
MANE Select: NM_030667
dbSNP: rs368334371
Type: single nucleotide variant
Location: chr12:15516954 (GRCh38)
Gene constraint: LOEUF 0.513 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 2 PDB
Residue 593: the fibronectin type-iii 6 domain

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

Similar variants

PTPRO p.Ala1086Val Uncertain significance ★★ ⚠ same type
PTPRO p.Ala591Thr Uncertain significance ★★ ⚠ same type
PTPRO p.Arg480Trp Uncertain significance ★★ same type
PTPRO p.Arg607Gln Uncertain significance ★★ ⚠ same type
PTPRO p.Asn569Asp Uncertain significance ★★ ⚠ same type
PTPRO p.Asp162Val Uncertain significance ★★ ⚠ same type
PTPRO p.Asp301His Uncertain significance ★★ ⚠ same type
PTPRO p.Asp799Gly Uncertain significance ★★ ⚠ same type

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-val593met (accessed [today's date]).

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