Is PTPRE p.Glu554Asp (c.1662G>C) pathogenic?

PTPRE p.Glu554Asp (c.1662G>C) is classified Uncertain significance in PTPRE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.2067); Ultra-rare (popmax 0.0205%, nfe).

How common is PTPRE p.Glu554Asp (c.1662G>C) in the general population?

PTPRE p.Glu554Asp (c.1662G>C) is ultra-rare (popmax 0.0205%, nfe) (gnomAD).

What do computational predictors say about PTPRE p.Glu554Asp (c.1662G>C)?

AlphaMissense predicts likely benign (score 0.2067) — an in-silico prediction, not a clinical call.

PTPRE p.Glu554Asp

c.1662G>C · VCV4573975

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2067 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0205%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2067	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.094	GERP -3, phastCons 0.013
Regional constraint	o/e 0.77	unconstrained · MANE · 35 kb · p 5.4e-11 · regional, not allelic
Overall
CADD	10.9	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 0.0205% European (non-Finnish) · 242/1,179,406 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0175%

Overall 0.0179% 288/1,611,630 alleles · ultra-rare exomes 258/1,459,360 · genomes 30/152,270 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.071%	1,408
European (non-Finnish)grpmax	0.0205%	4,874
Remaining individualsnot grpmax-eligible	0.0176%	5,672
Middle Eastern	0.0165%	6,058
Admixed American	0.0118%	8,446
Finnishnot grpmax-eligible	0.00625%	16,003
African / African-American	0.00267%	37,426

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PTPRE
Protein: p.Glu554Asp
Coding: c.1662G>C
MANE Select: NM_006504
Type: single nucleotide variant
Location: chr10:128076665 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.42 · 4 PDB
Residue 554: the tyrosine-protein phosphatase 2 domain; a β-strand

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

Similar variants

PTPRE p.Ala129Thr Uncertain significance ★ ⚠ same type
PTPRE p.Ala289Val Uncertain significance ★ ⚠ same type
PTPRE p.Ala328Ser Uncertain significance ★ ⚠ same type
PTPRE p.Ala578Thr Uncertain significance ★ ⚠ same type
PTPRE p.Ala602Thr Uncertain significance ★ ⚠ same type
PTPRE p.Ala65Val Uncertain significance ★ ⚠ same type
PTPRE p.Ala66Thr Uncertain significance ★ ⚠ same type
PTPRE p.Arg125His 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/ptpre-p-glu554asp (accessed [today's date]).

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