Is NF2 p.Leu46= (c.138C>A) pathogenic?

NF2 p.Leu46= (c.138C>A) is classified Likely benign in NF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-11). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Leu46= (c.138C>A)?

NF2 p.Leu46= (c.138C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Leu46= (c.138C>A) in the general population?

NF2 p.Leu46= (c.138C>A) is absent from gnomAD v4.1 (gnomAD).

NF2 p.Leu46=

c.138C>A · rs2065658819 · VCV1771493

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -4.3, phastCons 0.024
Overall
CADD	0.958	PHRED · no single calibrated threshold — expert panels disagree

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: NF2
Protein: p.Leu46=
Coding: c.138C>A
MANE Select: NM_000268
dbSNP: rs2065658819
Type: single nucleotide variant
Location: chr22:29636774 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 46: the ferm domain; a UniProt-annotated variant site (in vestibular schwannoma; loss of ability to interact with the cul4a-rbx1-ddb1-vprbp/dcaf1 e3 ubiquitin-protein ligase complex); an α-helix

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

Similar variants

NF2 c.1575-2A>G Pathogenic ★★ same condition
NF2 c.1737+1G>T Pathogenic ★★ same condition
NF2 c.1737+2T>C Pathogenic/Likely pathogenic ★★ same condition
NF2 c.240+1G>A Pathogenic/Likely pathogenic ★★ same condition
NF2 c.240+1G>C Pathogenic ★★ same condition
NF2 c.240+1G>T Pathogenic/Likely pathogenic ★★ same condition
NF2 c.363+2T>C Pathogenic/Likely pathogenic ★★ same condition
NF2 c.364-2A>G 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/nf2-p-leu46 (accessed [today's date]).

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