Is NF1 p.Pro464= (c.1392G>A) pathogenic?

NF1 p.Pro464= (c.1392G>A) is classified Conflicting classifications of pathogenicity in NF1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0379%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with NF1 p.Pro464= (c.1392G>A)?

NF1 p.Pro464= (c.1392G>A) is associated with hereditary neoplastic syndrome, neurofibromatosis, familial spinal, Watson syndrome (ClinVar).

How common is NF1 p.Pro464= (c.1392G>A) in the general population?

NF1 p.Pro464= (c.1392G>A) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

NF1 p.Pro464=

c.1392G>A · rs201604273 · VCV186095

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.78, phastCons 1
Overall
CADD	19.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,868 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00143% 23/1,613,452 alleles · ultra-rare exomes 21/1,461,270 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,639
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,861
Remaining individualsnot grpmax-eligible	0.0016%	62,470
African / African-American	0.00133%	74,976
European (non-Finnish)	8.48e-05%	1,179,549

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.Pro464=
Coding: c.1392G>A
MANE Select: NM_001042492
dbSNP: rs201604273
Type: single nucleotide variant
Location: chr17:31206371 (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, familial spinal Watson syndrome neurofibromatosis-Noonan syndrome juvenile myelomonocytic leukemia neurofibromatosis type 1

Similar variants

NF1 p.Pro464Leu Uncertain significance ★★ same residue
NF1 p.Pro464Arg Uncertain significance ★ ⚠ same residue
NF1 p.Pro464Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
NF1 p.Pro464Ser Uncertain significance ★ ⚠ 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-pro464 (accessed [today's date]).

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