Is NF2 p.Asp45His (c.133G>C) pathogenic?

NF2 p.Asp45His (c.133G>C) is classified Uncertain significance in NF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.9007); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Asp45His (c.133G>C)?

NF2 p.Asp45His (c.133G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Asp45His (c.133G>C) in the general population?

NF2 p.Asp45His (c.133G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NF2 p.Asp45His (c.133G>C)?

AlphaMissense predicts likely pathogenic (score 0.9007) — an in-silico prediction, not a clinical call.

NF2 p.Asp45His

c.133G>C · VCV4843848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9007 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9007	likely pathogenic
REVEL	0.496	indeterminate
SaProt	LLR -8.95	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	25.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NF2
Protein: p.Asp45His
Coding: c.133G>C
MANE Select: NM_000268
Type: single nucleotide variant
Location: chr22:29636769 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 45: the ferm domain; an α-helix

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

Similar variants

NF2 p.Asp45Asn Uncertain significance ★★ ⚠ same residue
NF2 p.Asp45Tyr Uncertain significance ★★ ⚠ same residue
NF2 p.Asp45= Likely benign ★★ same residue
NF2 p.Asp45Ala Uncertain significance ★ ⚠ same residue
NF2 p.Asp45Gly Uncertain significance ★ ⚠ same residue
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-asp45his (accessed [today's date]).

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