Is NF2 p.Val72Ala (c.215T>C) pathogenic?

NF2 p.Val72Ala (c.215T>C) is classified Conflicting classifications of pathogenicity in NF2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1264); Rare (popmax 0.116%, mid); Associated with NF2-related schwannomatosis.

What condition is associated with NF2 p.Val72Ala (c.215T>C)?

NF2 p.Val72Ala (c.215T>C) is associated with NF2-related schwannomatosis, familial meningioma, hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Val72Ala (c.215T>C) in the general population?

NF2 p.Val72Ala (c.215T>C) is rare (popmax 0.116%, mid) (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.Val72Ala (c.215T>C)?

AlphaMissense predicts likely benign (score 0.1264) — an in-silico prediction, not a clinical call.

NF2 p.Val72Ala

c.215T>C · rs1260510937 · VCV569354

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1264 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NF2-related schwannomatosis

Computational evidence

Protein change
AlphaMissense	0.1264	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -8.85	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 5.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	24.3	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 0.116% Middle Eastern · 7/6,038 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.000867% 14/1,614,140 alleles · rare exomes 14/1,461,864 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	863
Remaining individualsnot grpmax-eligible	0.0032%	31,251
South Asian	0.0011%	91,076
European (non-Finnish)	0.000339%	295,004

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.Val72Ala
Coding: c.215T>C
MANE Select: NM_000268
dbSNP: rs1260510937
Type: single nucleotide variant
Location: chr22:29636851 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB
Residue 72: the ferm domain; a β-strand

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

Disease context

Also linked: familial meningioma hereditary neoplastic syndrome SMARCB1-related schwannomatosis

For Full NF2-related schwannomatosis (Orphanet):

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

Similar variants

NF2 p.Val72= Likely benign ★★ 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
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-val72ala (accessed [today's date]).

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