Is NF2 p.Ala448Val (c.1343C>T) pathogenic?

NF2 p.Ala448Val (c.1343C>T) is classified Uncertain significance in NF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-07). AlphaMissense: likely benign (0.1913); Very rare (popmax 8.7e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Ala448Val (c.1343C>T)?

NF2 p.Ala448Val (c.1343C>T) is associated with hereditary neoplastic syndrome, NF2-related schwannomatosis (ClinVar).

How common is NF2 p.Ala448Val (c.1343C>T) in the general population?

NF2 p.Ala448Val (c.1343C>T) is very rare (popmax 8.7e-05%, nfe) (gnomAD).

What do computational predictors say about NF2 p.Ala448Val (c.1343C>T)?

AlphaMissense predicts likely benign (score 0.1913) — an in-silico prediction, not a clinical call.

NF2 p.Ala448Val

c.1343C>T · rs2066911555 · VCV1516937

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.7e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1913	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0072 · regional, not allelic
Overall
CADD	24.1	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

Grpmax group 8.7e-05% European (non-Finnish) · 1/1,148,940 alleles

Overall 7.13e-05% 1/1,403,474 alleles · very rare

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.Ala448Val
Coding: c.1343C>T
MANE Select: NM_000268
dbSNP: rs2066911555
Type: single nucleotide variant
Location: chr22:29674838 (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.Ala448Gly Uncertain significance ★★ ⚠ same residue
NF2 p.Ala448Thr 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

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-ala448val (accessed [today's date]).

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