Is PTPRF p.Pro712Leu (c.2135C>T) pathogenic?

PTPRF p.Pro712Leu (c.2135C>T) is classified Uncertain significance in PTPRF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.7982); Very rare (popmax 8.48e-05%, nfe).

How common is PTPRF p.Pro712Leu (c.2135C>T) in the general population?

PTPRF p.Pro712Leu (c.2135C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PTPRF p.Pro712Leu (c.2135C>T)?

AlphaMissense predicts likely pathogenic (score 0.7982) — an in-silico prediction, not a clinical call.

PTPRF p.Pro712Leu

c.2135C>T · VCV3940749

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7982	likely pathogenic
REVEL	0.682	pathogenic-leaning
SaProt	LLR -13.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 1,083 bp · p 2.4e-09 · regional, not allelic
Overall
CADD	28.0	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 8.48e-05% European (non-Finnish) · 1/1,179,546 alleles

Overall 6.2e-05% 1/1,613,506 alleles · very rare exomes 1/1,461,174 · genomes 0/152,332 · 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: PTPRF
Protein: p.Pro712Leu
Coding: c.2135C>T
MANE Select: NM_002840
Type: single nucleotide variant
Location: chr1:43598735 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.43 · 13 PDB
Residue 712: an α-helix; the fibronectin type-iii 5 domain; the 'disordered' region

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

Similar variants

PTPRF p.Gly1143Ser Uncertain significance ★★ ⚠ same type
PTPRF p.His1730Gln Uncertain significance ★★ ⚠ same type
PTPRF c.1531+9G>A Benign/Likely benign ★★ same type
PTPRF c.1668+10G>C Benign/Likely benign ★★ same type
PTPRF c.237+5G>A Benign ★★ same type
PTPRF c.3974-9C>T Benign ★★ same type
PTPRF p.Ala1659= Benign ★★ same type
PTPRF p.Ala356Ser Likely benign ★★ 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/ptprf-p-pro712leu (accessed [today's date]).

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