Is NF2 p.Ala323Val (c.968C>T) pathogenic?

NF2 p.Ala323Val (c.968C>T) is classified Uncertain significance in NF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: ambiguous (0.3655); Very rare (popmax 0.00167%, amr); Associated with NF2-related schwannomatosis.

What condition is associated with NF2 p.Ala323Val (c.968C>T)?

NF2 p.Ala323Val (c.968C>T) is associated with NF2-related schwannomatosis (ClinVar).

How common is NF2 p.Ala323Val (c.968C>T) in the general population?

NF2 p.Ala323Val (c.968C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Full NF2-related schwannomatosis inherited?

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

What do computational predictors say about NF2 p.Ala323Val (c.968C>T)?

AlphaMissense predicts ambiguous (score 0.3655) — an in-silico prediction, not a clinical call.

NF2 p.Ala323Val

c.968C>T · VCV4706472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

NF2-related schwannomatosis

Computational evidence

Protein change
AlphaMissense	0.3655	ambiguous
REVEL	0.542	indeterminate
SaProt	LLR -9.96	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	26.1	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 0.00167% Admixed American · 1/60,008 alleles

Overall 0.000205% 3/1,461,574 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.48e-05%	1,179,792

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.Ala323Val
Coding: c.968C>T
MANE Select: NM_000268
Type: single nucleotide variant
Location: chr22:29668415 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 323: an α-helix

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

Disease context

NF2-related schwannomatosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Full NF2-related schwannomatosis (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NF2 p.Ala323Gly Uncertain significance ★ 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-ala323val (accessed [today's date]).

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