Is PTPRF p.Pro459Leu (c.1376C>T) pathogenic?

PTPRF p.Pro459Leu (c.1376C>T) is classified Likely benign in PTPRF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely benign (0.0421); Ultra-rare (popmax 0.0166%, eas).

How common is PTPRF p.Pro459Leu (c.1376C>T) in the general population?

PTPRF p.Pro459Leu (c.1376C>T) is ultra-rare (popmax 0.0166%, eas) (gnomAD).

What do computational predictors say about PTPRF p.Pro459Leu (c.1376C>T)?

AlphaMissense predicts likely benign (score 0.0421) — an in-silico prediction, not a clinical call.

PTPRF p.Pro459Leu

c.1376C>T · VCV3785215

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0421 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0421	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -0.02	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 5.1	GERP -1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 6,728 bp · p 0.011 · regional, not allelic
Overall
CADD	15.77	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 0.0166% East Asian · 7/42,110 alleles

Filtering AF 0.00778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00552%

Overall 0.00179% 28/1,565,486 alleles · ultra-rare exomes 25/1,413,228 · genomes 3/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0166%	6,016
African / African-American	0.0122%	8,199
Admixed American	0.00375%	26,681
Finnishnot grpmax-eligible	0.00347%	28,780
Remaining individualsnot grpmax-eligible	0.00165%	60,726
European (non-Finnish)	0.000605%	165,234

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.Pro459Leu
Coding: c.1376C>T
MANE Select: NM_002840
Type: single nucleotide variant
Location: chr1:43591398 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.43 · 13 PDB
Residue 459: an α-helix; the fibronectin type-iii 2 domain

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

Similar variants

PTPRF p.Pro459= Likely benign same residue
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

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-pro459leu (accessed [today's date]).

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