Is NF1 p.Ala548Pro (c.1642G>C) pathogenic?

NF1 p.Ala548Pro (c.1642G>C) is classified Conflicting classifications of pathogenicity in NF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with neurofibromatosis type 1.

What condition is associated with NF1 p.Ala548Pro (c.1642G>C)?

NF1 p.Ala548Pro (c.1642G>C) is associated with neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Ala548Pro (c.1642G>C) in the general population?

NF1 p.Ala548Pro (c.1642G>C) is absent from gnomAD v4.1 (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.Ala548Pro (c.1642G>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

NF1 p.Ala548Pro

c.1642G>C · rs2066927450 · VCV2832382

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

neurofibromatosis type 1

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 1% in NF1
REVEL	0.514	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Pangolin	Δ0.23	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 41 kb · p 4.2e-25 · regional, not allelic
Overall
CADD	33.0	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

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: NF1
Protein: p.Ala548Pro
Coding: c.1642G>C
MANE Select: NM_001042492
dbSNP: rs2066927450
Type: single nucleotide variant
Location: chr17:31221850 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 548: an α-helix

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.Ala548Thr Uncertain significance ★★ ⚠ same residue
NF1 p.Ala548Val Uncertain significance ★★ ⚠ same residue
NF1 p.Ala548Ser Conflicting classifications of pathogenicity ★ same residue
NF1 p.Ala548= Likely benign ★ 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-ala548pro (accessed [today's date]).

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