Is NF2 p.Ala2Ser (c.4G>T) pathogenic?

NF2 p.Ala2Ser (c.4G>T) is classified Uncertain significance in NF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.3149); No allele count reported in gnomAD v4.1 (AN 1,581,458); Associated with SMARCB1-related schwannomatosis.

What condition is associated with NF2 p.Ala2Ser (c.4G>T)?

NF2 p.Ala2Ser (c.4G>T) is associated with SMARCB1-related schwannomatosis, NF2-related schwannomatosis, familial meningioma (ClinVar).

How common is NF2 p.Ala2Ser (c.4G>T) in the general population?

NF2 p.Ala2Ser (c.4G>T) is no allele count reported in gnomAD v4.1 (AN 1,581,458) (gnomAD).

How is Full schwannomatosis inherited?

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

What do computational predictors say about NF2 p.Ala2Ser (c.4G>T)?

AlphaMissense predicts likely benign (score 0.3149) — an in-silico prediction, not a clinical call.

NF2 p.Ala2Ser

c.4G>T · rs1601515682 · VCV638486

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3149 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,581,458)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

SMARCB1-related schwannomatosis

Computational evidence

Protein change
AlphaMissense	0.3149	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -5.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.31, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,581,458). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NF2
Protein: p.Ala2Ser
Coding: c.4G>T
MANE Select: NM_000268
dbSNP: rs1601515682
Type: single nucleotide variant
Location: chr22:29604002 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB

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

Disease context

Also linked: NF2-related schwannomatosis familial meningioma

For Full schwannomatosis (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

NF2 p.Ala2= 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
NF2 c.1737+2T>C Pathogenic/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-ala2ser (accessed [today's date]).

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