Is NF1 p.Pro22Ala (c.64C>G) pathogenic?

NF1 p.Pro22Ala (c.64C>G) is classified Uncertain significance in NF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-26). AlphaMissense: likely pathogenic (0.9257); No allele count reported in gnomAD v4.1 (AN 1,601,370); Associated with neurofibromatosis type 1.

What condition is associated with NF1 p.Pro22Ala (c.64C>G)?

NF1 p.Pro22Ala (c.64C>G) is associated with neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Pro22Ala (c.64C>G) in the general population?

NF1 p.Pro22Ala (c.64C>G) is no allele count reported in gnomAD v4.1 (AN 1,601,370) (gnomAD).

How is Neurofibromatosis type 1 inherited?

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

What do computational predictors say about NF1 p.Pro22Ala (c.64C>G)?

AlphaMissense predicts likely pathogenic (score 0.9257) — an in-silico prediction, not a clinical call.

NF1 p.Pro22Ala

c.64C>G · rs1597625794 · VCV837341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9257 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,601,370)

Conditions

neurofibromatosis type 1

Computational evidence

Protein change
AlphaMissense	0.9257	likely pathogenic
REVEL	0.409	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 4.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 87 kb · p 4.8e-08 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,601,370). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NF1
Protein: p.Pro22Ala
Coding: c.64C>G
MANE Select: NM_001042492
dbSNP: rs1597625794
Type: single nucleotide variant
Location: chr17:31155986 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

Full NF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurofibromatosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Neurofibromatosis type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-5 / 10 000 (United Kingdom)

Similar variants

NF1 p.Pro22Leu Uncertain significance ★★ same residue
NF1 p.Pro22= Likely benign ★★ same residue
NF1 p.Pro22Ser Conflicting classifications of pathogenicity ★ same residue
NF1 p.Pro22fs Pathogenic ★ same residue
NF1 c.1062+1G>A Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+1G>C Pathogenic ★★ same condition
NF1 c.1062+2T>A Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+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/nf1-p-pro22ala (accessed [today's date]).

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