Is PTPN11 p.Val415Phe (c.1243G>T) pathogenic?

PTPN11 p.Val415Phe (c.1243G>T) is classified Uncertain significance in PTPN11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-02). AlphaMissense: likely pathogenic (0.9915); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with PTPN11 p.Val415Phe (c.1243G>T)?

PTPN11 p.Val415Phe (c.1243G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is PTPN11 p.Val415Phe (c.1243G>T) in the general population?

PTPN11 p.Val415Phe (c.1243G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTPN11 p.Val415Phe (c.1243G>T)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

PTPN11 p.Val415Phe

c.1243G>T · VCV3784976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic
REVEL	0.977	strongly pathogenic-leaning
SaProt	LLR -14.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 16 kb · p 1e-18 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PTPN11
Protein: p.Val415Phe
Coding: c.1243G>T
MANE Select: NM_002834
Type: single nucleotide variant
Location: chr12:112486493 (GRCh38)
Gene constraint: LOEUF 0.156 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.34 · 117 PDB
Residue 415: a β-strand; the tyrosine-protein phosphatase domain

Full PTPN11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PTPN11 p.Ala72Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
PTPN11 p.Arg231Ter Pathogenic/Likely pathogenic ★★ same condition
PTPN11 p.Arg265Leu Likely pathogenic ★★ same condition
PTPN11 p.Asp61His Pathogenic ★★ same condition
PTPN11 p.Gln256Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
PTPN11 p.Glu110Ala Pathogenic/Likely pathogenic ★★ ⚠ same condition
PTPN11 p.Gly60Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
PTPN11 p.Ile282Met Pathogenic/Likely pathogenic ★★ 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/ptpn11-p-val415phe (accessed [today's date]).

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