Is NF2 p.Ala4Pro (c.10G>C) pathogenic?

NF2 p.Ala4Pro (c.10G>C) is classified Uncertain significance in NF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: ambiguous (0.5328); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with NF2 p.Ala4Pro (c.10G>C)?

NF2 p.Ala4Pro (c.10G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is NF2 p.Ala4Pro (c.10G>C) in the general population?

NF2 p.Ala4Pro (c.10G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NF2 p.Ala4Pro (c.10G>C)?

AlphaMissense predicts ambiguous (score 0.5328) — an in-silico prediction, not a clinical call.

NF2 p.Ala4Pro

c.10G>C · rs2146659577 · VCV3231069

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5328 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5328	ambiguous
REVEL	0.485	indeterminate
SaProt	LLR -6.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 69 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	26.0	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.Ala4Pro
Coding: c.10G>C
MANE Select: NM_000268
dbSNP: rs2146659577
Type: single nucleotide variant
Location: chr22:29604008 (GRCh38)
Gene constraint: LOEUF 0.187 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 6 PDB

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.Ala4Ser Uncertain significance ★★ ⚠ same residue
NF2 p.Ala4= Benign/Likely benign ★★ 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
NF2 c.240+1G>A Pathogenic/Likely pathogenic ★★ same condition
NF2 c.240+1G>C Pathogenic ★★ same condition
NF2 c.240+1G>T 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-ala4pro (accessed [today's date]).

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