Is NF2 p.Ala464Val (c.1391C>T) pathogenic?

NF2 p.Ala464Val (c.1391C>T) is classified Conflicting classifications of pathogenicity in NF2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.3009); Very rare (popmax 0.00468%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Ala464Val (c.1391C>T)?

NF2 p.Ala464Val (c.1391C>T) is associated with hereditary neoplastic syndrome, NF2-related schwannomatosis (ClinVar).

How common is NF2 p.Ala464Val (c.1391C>T) in the general population?

NF2 p.Ala464Val (c.1391C>T) is very rare (popmax 0.00468%, sas) (gnomAD).

What do computational predictors say about NF2 p.Ala464Val (c.1391C>T)?

AlphaMissense predicts likely benign (score 0.3009) — an in-silico prediction, not a clinical call.

NF2 p.Ala464Val

c.1391C>T · rs776109136 · VCV457898

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3009 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00468%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3009	likely benign
REVEL	0.514	indeterminate
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0072 · 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 0.00468% South Asian · 4/85,528 alleles

Filtering AF 0.00159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000936%

Overall 0.000699% 11/1,573,916 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00468%	21,382
East Asian	0.00233%	42,922
African / African-American	0.00135%	74,084
European (non-Finnish)	0.000431%	231,780

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.Ala464Val
Coding: c.1391C>T
MANE Select: NM_000268
dbSNP: rs776109136
Type: single nucleotide variant
Location: chr22:29674886 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: NF2-related schwannomatosis

Similar variants

NF2 p.Ala464Glu Uncertain significance ★★ same residue
NF2 p.Ala464= Benign/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

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-ala464val (accessed [today's date]).

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