Is PTPRR p.Pro558Ser (c.1672C>T) pathogenic?

PTPRR p.Pro558Ser (c.1672C>T) is classified Uncertain significance in PTPRR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.9948); Very rare (popmax 0.00133%, afr).

How common is PTPRR p.Pro558Ser (c.1672C>T) in the general population?

PTPRR p.Pro558Ser (c.1672C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PTPRR p.Pro558Ser (c.1672C>T)?

AlphaMissense predicts likely pathogenic (score 0.9948) — an in-silico prediction, not a clinical call.

PTPRR p.Pro558Ser

c.1672C>T · VCV4574206

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9948	likely pathogenic · top 5% in PTPRR
REVEL	0.707	pathogenic-leaning
SaProt	LLR -12.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 45 kb · p 0.006 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,922 alleles

Overall 6.2e-05% 1/1,613,422 alleles · very rare exomes 0/1,461,210 · genomes 1/152,212 · joint denominator

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: PTPRR
Protein: p.Pro558Ser
Coding: c.1672C>T
MANE Select: NM_002849
Type: single nucleotide variant
Location: chr12:70661034 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 1 PDB
Residue 558: the tyrosine-protein phosphatase domain

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

Similar variants

PTPRR p.Ala295Thr Uncertain significance ★ ⚠ same type
PTPRR p.Ala318Thr Uncertain significance ★ ⚠ same type
PTPRR p.Ala367Glu Uncertain significance ★ ⚠ same type
PTPRR p.Ala388Thr Uncertain significance ★ ⚠ same type
PTPRR p.Ala461Asp Uncertain significance ★ same type
PTPRR p.Ala577Gly Uncertain significance ★ ⚠ same type
PTPRR p.Ala616Val Uncertain significance ★ ⚠ same type
PTPRR p.Ala653Thr 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/ptprr-p-pro558ser (accessed [today's date]).

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