Is PTPRF p.Val449Ile (c.1345G>A) pathogenic?

PTPRF p.Val449Ile (c.1345G>A) is classified Uncertain significance in PTPRF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely benign (0.1374); Ultra-rare (popmax 0.0315%, eas).

How common is PTPRF p.Val449Ile (c.1345G>A) in the general population?

PTPRF p.Val449Ile (c.1345G>A) is ultra-rare (popmax 0.0315%, eas) (gnomAD).

What do computational predictors say about PTPRF p.Val449Ile (c.1345G>A)?

AlphaMissense predicts likely benign (score 0.1374) — an in-silico prediction, not a clinical call.

PTPRF p.Val449Ile

c.1345G>A · VCV3428023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0315%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1374	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -7.75	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 6.7	GERP -0.006, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 6,728 bp · p 0.011 · regional, not allelic
Overall
CADD	22.8	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 0.0315% East Asian · 13/41,274 alleles

Filtering AF 0.0186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.00527% 82/1,555,424 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0315%	3,175
African / African-American	0.0218%	4,589
European (non-Finnish)	0.00417%	23,976
Admixed American	0.00386%	25,900
South Asian	0.00235%	42,521
Remaining individualsnot grpmax-eligible	0.00166%	60,304

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.Val449Ile
Coding: c.1345G>A
MANE Select: NM_002840
Type: single nucleotide variant
Location: chr1:43591367 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.43 · 13 PDB
Residue 449: a β-strand; the fibronectin type-iii 2 domain

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-val449ile (accessed [today's date]).

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