Is NF2 p.Arg554Thr (c.1661G>C) pathogenic?

NF2 p.Arg554Thr (c.1661G>C) is classified Uncertain significance in NF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.7126); Very rare (popmax 8.47e-05%, nfe); Associated with NF2-related schwannomatosis.

What condition is associated with NF2 p.Arg554Thr (c.1661G>C)?

NF2 p.Arg554Thr (c.1661G>C) is associated with NF2-related schwannomatosis, hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Arg554Thr (c.1661G>C) in the general population?

NF2 p.Arg554Thr (c.1661G>C) is very rare (popmax 8.47e-05%, nfe) (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.Arg554Thr (c.1661G>C)?

AlphaMissense predicts likely pathogenic (score 0.7126) — an in-silico prediction, not a clinical call.

NF2 p.Arg554Thr

c.1661G>C · rs2067134618 · VCV2453841

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

NF2-related schwannomatosis

Computational evidence

Protein change
AlphaMissense	0.7126	likely pathogenic
REVEL	0.584	indeterminate
SaProt	LLR -8.42	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 10	GERP 2.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0072 · regional, not allelic
Overall
CADD	24.9	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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.2e-05% 1/1,614,198 alleles · very rare exomes 1/1,461,884 · genomes 0/152,314 · joint denominator

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.Arg554Thr
Coding: c.1661G>C
MANE Select: NM_000268
dbSNP: rs2067134618
Type: single nucleotide variant
Location: chr22:29681525 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 554: an α-helix

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

Disease context

Also linked: hereditary neoplastic syndrome

For Full NF2-related schwannomatosis (Orphanet):

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

Similar variants

NF2 p.Arg554Gly Uncertain significance ★★ same residue
NF2 p.Arg554Lys Uncertain significance ★★ ⚠ same residue
NF2 p.Arg554= Likely benign ★★ same residue
NF2 p.Arg554Trp Uncertain significance ★ ⚠ same residue
NF2 p.Arg554fs Pathogenic ★ 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

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-arg554thr (accessed [today's date]).

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