Is NF2 p.Pro252Ala (c.754C>G) pathogenic?

NF2 p.Pro252Ala (c.754C>G) is classified Uncertain significance in NF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-28). AlphaMissense: ambiguous (0.4196); Ultra-rare (popmax 0.0223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Pro252Ala (c.754C>G)?

NF2 p.Pro252Ala (c.754C>G) is associated with hereditary neoplastic syndrome, NF2-related schwannomatosis, familial meningioma (ClinVar).

How common is NF2 p.Pro252Ala (c.754C>G) in the general population?

NF2 p.Pro252Ala (c.754C>G) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about NF2 p.Pro252Ala (c.754C>G)?

AlphaMissense predicts ambiguous (score 0.4196) — an in-silico prediction, not a clinical call.

NF2 p.Pro252Ala

c.754C>G · rs2066469878 · VCV1516736

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4196 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4196	ambiguous
REVEL	0.631	indeterminate
SaProt	LLR -10.92	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	25.4	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 0.0223% East Asian · 10/44,880 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000684% 10/1,461,882 alleles · ultra-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.Pro252Ala
Coding: c.754C>G
MANE Select: NM_000268
dbSNP: rs2066469878
Type: single nucleotide variant
Location: chr22:29661283 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 252: the ferm domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: NF2-related schwannomatosis familial meningioma

Similar variants

NF2 p.Pro252Ser Uncertain significance ★ ⚠ same residue
NF2 p.Pro252= 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-pro252ala (accessed [today's date]).

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