Is NF1 p.Pro563Ser (c.1687C>T) pathogenic?

NF1 p.Pro563Ser (c.1687C>T) is classified Uncertain significance in NF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-28). AlphaMissense: likely pathogenic (0.7309); Very rare (popmax 0.0033%, sas); Associated with juvenile myelomonocytic leukemia.

What condition is associated with NF1 p.Pro563Ser (c.1687C>T)?

NF1 p.Pro563Ser (c.1687C>T) is associated with juvenile myelomonocytic leukemia, neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Pro563Ser (c.1687C>T) in the general population?

NF1 p.Pro563Ser (c.1687C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

How is Juvenile myelomonocytic leukemia inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NF1 p.Pro563Ser (c.1687C>T)?

AlphaMissense predicts likely pathogenic (score 0.7309) — an in-silico prediction, not a clinical call.

NF1 p.Pro563Ser

c.1687C>T · rs2066928705 · VCV966412

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7309 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Conditions

juvenile myelomonocytic leukemia

Computational evidence

Protein change
AlphaMissense	0.7309	likely pathogenic
REVEL	0.391	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 41 kb · p 4.2e-25 · regional, not allelic
Overall
CADD	26.1	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

Grpmax group 0.0033% South Asian · 3/90,828 alleles

Filtering AF 0.000877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000187% 3/1,606,720 alleles · very rare exomes 3/1,454,540 · genomes 0/152,180 · 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.Pro563Ser
Coding: c.1687C>T
MANE Select: NM_001042492
dbSNP: rs2066928705
Type: single nucleotide variant
Location: chr17:31221895 (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

juvenile myelomonocytic leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurofibromatosis type 1

For Juvenile myelomonocytic leukemia (Orphanet):

Inheritance: Not applicable
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

NF1 p.Pro563= Likely benign ★★ same residue
NF1 p.Pro563Thr 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
NF1 c.1062+3A>G Pathogenic/Likely pathogenic ★★ same condition
NF1 c.1062+3A>T 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-pro563ser (accessed [today's date]).

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