Is NF2 p.Pro19Arg (c.56C>G) pathogenic?

NF2 p.Pro19Arg (c.56C>G) is classified Uncertain significance in NF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-18). AlphaMissense: likely benign (0.2896); Very rare (popmax 8.5e-05%, nfe); Associated with NF2-related schwannomatosis.

What condition is associated with NF2 p.Pro19Arg (c.56C>G)?

NF2 p.Pro19Arg (c.56C>G) is associated with NF2-related schwannomatosis, hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Pro19Arg (c.56C>G) in the general population?

NF2 p.Pro19Arg (c.56C>G) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

How is Full NF2-related schwannomatosis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NF2 p.Pro19Arg (c.56C>G)?

AlphaMissense predicts likely benign (score 0.2896) — an in-silico prediction, not a clinical call.

NF2 p.Pro19Arg

c.56C>G · rs1601515928 · VCV825907

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

NF2-related schwannomatosis

Computational evidence

Protein change
AlphaMissense	0.2896	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -10.65	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.46, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	25.3	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 8.5e-05% European (non-Finnish) · 1/1,177,082 alleles

Overall 6.87e-05% 1/1,455,072 alleles · very rare

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: NF2
Protein: p.Pro19Arg
Coding: c.56C>G
MANE Select: NM_000268
dbSNP: rs1601515928
Type: single nucleotide variant
Location: chr22:29604054 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB

Full NF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary neoplastic syndrome

For Full NF2-related schwannomatosis (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NF2 p.Pro19Ser Uncertain significance ★★ ⚠ same residue
NF2 p.Pro19= Likely benign ★★ same residue
NF2 c.115-1G>A Likely pathogenic ★★ same condition
NF2 c.1340+1G>T Pathogenic ★★ same condition
NF2 c.1340+2T>G Pathogenic ★★ same condition
NF2 c.1447-1G>A Pathogenic ★★ same condition
NF2 c.1575-2A>G Pathogenic ★★ same condition
NF2 c.1737+1G>T 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/nf2-p-pro19arg (accessed [today's date]).

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