Is NF2 p.Leu339= (c.1017C>T) pathogenic?

NF2 p.Leu339= (c.1017C>T) is classified Likely benign in NF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-11). Very rare (popmax 0.00223%, eas); Associated with NF2-related schwannomatosis.

What condition is associated with NF2 p.Leu339= (c.1017C>T)?

NF2 p.Leu339= (c.1017C>T) is associated with NF2-related schwannomatosis, hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Leu339= (c.1017C>T) in the general population?

NF2 p.Leu339= (c.1017C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Full NF2-related schwannomatosis inherited?

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

NF2 p.Leu339=

c.1017C>T · rs756568857 · VCV1142310

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

NF2-related schwannomatosis

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 -12	GERP -4
Overall
CADD	0.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,613,904 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
South Asian	0.0022%	45,540
European (non-Finnish)	0.000593%	168,569

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.Leu339=
Coding: c.1017C>T
MANE Select: NM_000268
dbSNP: rs756568857
Type: single nucleotide variant
Location: chr22:29671843 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 339: a UniProt-annotated variant site (in sporadic meningioma)

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.Leu339Arg Uncertain significance ★★ ⚠ same residue
NF2 p.Leu339fs 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-leu339 (accessed [today's date]).

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