Is NF1 p.Pro98Arg (c.293C>G) pathogenic?

NF1 p.Pro98Arg (c.293C>G) is classified Uncertain significance in NF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-18). AlphaMissense: ambiguous (0.5471); Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with NF1 p.Pro98Arg (c.293C>G)?

NF1 p.Pro98Arg (c.293C>G) is associated with hereditary neoplastic syndrome, neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Pro98Arg (c.293C>G) in the general population?

NF1 p.Pro98Arg (c.293C>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about NF1 p.Pro98Arg (c.293C>G)?

AlphaMissense predicts ambiguous (score 0.5471) — an in-silico prediction, not a clinical call.

NF1 p.Pro98Arg

c.293C>G · rs780979519 · VCV1797898

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5471 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5471	ambiguous
REVEL	0.612	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 87 kb · p 4.8e-08 · regional, not allelic
Overall
CADD	23.9	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

Grpmax group 0.0022% South Asian · 2/91,030 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,784 alleles · very rare exomes 2/1,461,662 · genomes 0/152,122 · joint denominator

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: NF1
Protein: p.Pro98Arg
Coding: c.293C>G
MANE Select: NM_001042492
dbSNP: rs780979519
Type: single nucleotide variant
Location: chr17:31163190 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurofibromatosis type 1

Similar variants

NF1 p.Pro98Gln Uncertain significance ★★ same residue
NF1 p.Pro98= Likely benign ★★ same residue
NF1 p.Pro98Ala Uncertain significance ★ same residue
NF1 p.Pro98Leu Uncertain significance ★ same residue
NF1 p.Pro98Ser Uncertain significance ★ same residue
NF1 p.Pro98Thr Uncertain significance ★ same residue
NF1 c.1062+1G>A Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+1G>C 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-pro98arg (accessed [today's date]).

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