Is NF2 p.Ala557= (c.1671T>C) pathogenic?

NF2 p.Ala557= (c.1671T>C) is classified Likely benign in NF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-27). Very rare (popmax 0.00329%, sas); Associated with NF2-related schwannomatosis.

What condition is associated with NF2 p.Ala557= (c.1671T>C)?

NF2 p.Ala557= (c.1671T>C) is associated with NF2-related schwannomatosis, hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Ala557= (c.1671T>C) in the general population?

NF2 p.Ala557= (c.1671T>C) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Full NF2-related schwannomatosis inherited?

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

NF2 p.Ala557=

c.1671T>C · rs759780271 · VCV237622

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

NF2-related schwannomatosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.75	GERP -4.6
Overall
CADD	3.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,614,190 alleles · very rare exomes 4/1,461,888 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,362
European (non-Finnish)	8.47e-05%	1,180,027

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.Ala557=
Coding: c.1671T>C
MANE Select: NM_000268
dbSNP: rs759780271
Type: single nucleotide variant
Location: chr22:29681535 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 557: 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.Ala557Thr Uncertain significance ★★ ⚠ same residue
NF2 p.Ala557Asp Uncertain significance ★ ⚠ same residue
NF2 p.Ala557Gly 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

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-ala557 (accessed [today's date]).

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