Is PTPRF p.Pro399Leu (c.1196C>T) pathogenic?

PTPRF p.Pro399Leu (c.1196C>T) is classified Likely benign in PTPRF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-02-09). AlphaMissense: likely benign (0.1127); Ultra-rare (popmax 0.0166%, mid); Associated with PTPRF-related disorder.

What condition is associated with PTPRF p.Pro399Leu (c.1196C>T)?

PTPRF p.Pro399Leu (c.1196C>T) is associated with PTPRF-related disorder (ClinVar).

How common is PTPRF p.Pro399Leu (c.1196C>T) in the general population?

PTPRF p.Pro399Leu (c.1196C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about PTPRF p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely benign (score 0.1127) — an in-silico prediction, not a clinical call.

PTPRF p.Pro399Leu

c.1196C>T · rs61733187 · VCV3051560

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1127 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PTPRF-related disorder

Computational evidence

Protein change
AlphaMissense	0.1127	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 6,728 bp · p 0.011 · regional, not allelic
Overall
CADD	25.7	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% Middle Eastern · 1/6,012 alleles

Filtering AF 0.0126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.0171% 275/1,603,760 alleles · ultra-rare exomes 237/1,451,390 · genomes 38/152,370 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.228%	439
Remaining individualsnot grpmax-eligible	0.029%	3,447
Middle Easterngrpmax	0.0166%	6,012
Admixed American	0.0151%	6,624
European (non-Finnish)	0.0145%	6,913
African / African-American	0.00667%	14,982
South Asian	0.00551%	18,148

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: PTPRF
Protein: p.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_002840
dbSNP: rs61733187
Type: single nucleotide variant
Location: chr1:43591218 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.43 · 13 PDB
Residue 399: the 'disordered' region; an α-helix; the fibronectin type-iii 1 domain

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

Disease context

PTPRF-related disorder

Similar variants

PTPRF c.3389+4T>G Likely benign same condition
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PTPRF c.4372-7C>T Likely benign same condition
PTPRF p.Ala157= Benign same condition
PTPRF p.Arg1286= Likely benign same condition
PTPRF p.Asn441= Likely benign same condition
PTPRF p.Asp562Asn Benign same condition
PTPRF p.Asp650= Likely benign same condition

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-pro399leu (accessed [today's date]).

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