Is NF2 p.Glu463= (c.1389G>A) pathogenic?

NF2 p.Glu463= (c.1389G>A) is classified Likely benign in NF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-11). Very rare (popmax 0.00135%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Glu463= (c.1389G>A)?

NF2 p.Glu463= (c.1389G>A) is associated with hereditary neoplastic syndrome, NF2-related schwannomatosis (ClinVar).

How common is NF2 p.Glu463= (c.1389G>A) in the general population?

NF2 p.Glu463= (c.1389G>A) is very rare (popmax 0.00135%, afr) (gnomAD).

NF2 p.Glu463=

c.1389G>A · rs1321208414 · VCV1771482

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.196	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -4.4, phastCons 1
Overall
CADD	0.893	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00135% African / African-American · 1/74,076 alleles

Overall 0.000191% 3/1,573,708 alleles · very rare exomes 1/1,421,508 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,076
South Asian	0.00117%	85,498
European (non-Finnish)	8.63e-05%	1,158,753

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.Glu463=
Coding: c.1389G>A
MANE Select: NM_000268
dbSNP: rs1321208414
Type: single nucleotide variant
Location: chr22:29674884 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 463: a UniProt-annotated variant site (in a breast cancer sample; somatic mutation)

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

Similar variants

NF2 p.Glu463Lys Benign/Likely benign ★★ ⚠ same residue
NF2 p.Glu463Ter Pathogenic ★ 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-glu463 (accessed [today's date]).

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