Is NF1 p.Ser666= (c.1998T>C) pathogenic?

NF1 p.Ser666= (c.1998T>C) is classified Conflicting classifications of pathogenicity in NF1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-05-15). Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with NF1 p.Ser666= (c.1998T>C)?

NF1 p.Ser666= (c.1998T>C) is associated with hereditary neoplastic syndrome, neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Ser666= (c.1998T>C) in the general population?

NF1 p.Ser666= (c.1998T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

NF1 p.Ser666=

c.1998T>C · rs1567846823 · VCV561687

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.97	GERP -0.87
Overall
CADD	9.289	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,580 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,582 alleles · very rare exomes 3/1,461,260 · genomes 0/152,322 · 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.Ser666=
Coding: c.1998T>C
MANE Select: NM_001042492
dbSNP: rs1567846823
Type: single nucleotide variant
Location: chr17:31225247 (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.Ser666Ala Uncertain significance ★★ ⚠ same residue
NF1 p.Ser666Pro Uncertain significance ★★ ⚠ same residue
NF1 p.Ser666Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
NF1 p.Ser666Thr Likely benign ★ same residue
NF1 p.Ser666fs Pathogenic ★ same residue
NF1 p.Ser666Tyr 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-ser666 (accessed [today's date]).

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