Is NF2 p.Pro181= (c.543G>A) pathogenic?

NF2 p.Pro181= (c.543G>A) is classified Likely benign in NF2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-10). Very rare (popmax 0.00659%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Pro181= (c.543G>A)?

NF2 p.Pro181= (c.543G>A) is associated with hereditary neoplastic syndrome, NF2-related schwannomatosis (ClinVar).

How common is NF2 p.Pro181= (c.543G>A) in the general population?

NF2 p.Pro181= (c.543G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

NF2 p.Pro181=

c.543G>A · rs139838280 · VCV527719

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Conditions

hereditary neoplastic syndrome

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 -1.9	GERP -3.6
Overall
CADD	11.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,066 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00421% 68/1,613,750 alleles · very rare exomes 66/1,461,778 · genomes 2/151,972 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
European (non-Finnish)	0.00517%	19,343
African / African-American	0.00134%	74,868

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.Pro181=
Coding: c.543G>A
MANE Select: NM_000268
dbSNP: rs139838280
Type: single nucleotide variant
Location: chr22:29655620 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 181: 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

Also linked: NF2-related schwannomatosis

Similar variants

NF2 p.Pro181Ala Uncertain significance ★ ⚠ same residue
NF2 p.Pro181Arg Uncertain significance ★ ⚠ same residue
NF2 p.Pro181Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NF2 p.Pro181Ser 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

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-pro181 (accessed [today's date]).

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