Is NF2 p.Pro91Arg (c.272C>G) pathogenic?

NF2 p.Pro91Arg (c.272C>G) is classified Uncertain significance in NF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). AlphaMissense: likely pathogenic (0.5927); Very rare (popmax 8.47e-05%, nfe); Associated with NF2-related schwannomatosis.

What condition is associated with NF2 p.Pro91Arg (c.272C>G)?

NF2 p.Pro91Arg (c.272C>G) is associated with NF2-related schwannomatosis, hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Pro91Arg (c.272C>G) in the general population?

NF2 p.Pro91Arg (c.272C>G) is very rare (popmax 8.47e-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.Pro91Arg (c.272C>G)?

AlphaMissense predicts likely pathogenic (score 0.5927) — an in-silico prediction, not a clinical call.

NF2 p.Pro91Arg

c.272C>G · rs1569281659 · VCV971447

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

NF2-related schwannomatosis

Computational evidence

Protein change
AlphaMissense	0.5927	likely pathogenic
REVEL	0.569	indeterminate
SaProt	LLR -12.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	28.6	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.84e-05% 1/1,461,878 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.Pro91Arg
Coding: c.272C>G
MANE Select: NM_000268
dbSNP: rs1569281659
Type: single nucleotide variant
Location: chr22:29639121 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 91: the ferm domain; a β-strand

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.Pro91Gln Uncertain significance ★★ same residue
NF2 p.Pro91= Likely benign ★★ same residue
NF2 p.Pro91Thr Uncertain significance ★ ⚠ same residue
NF2 p.Pro91Ser Uncertain significance ★ 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

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-pro91arg (accessed [today's date]).

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