Is NF1 p.Ser665Phe (c.1994C>T) pathogenic?

NF1 p.Ser665Phe (c.1994C>T) is classified Conflicting classifications of pathogenicity in NF1 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1215); Rare (popmax 0.665%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with NF1 p.Ser665Phe (c.1994C>T)?

NF1 p.Ser665Phe (c.1994C>T) is associated with hereditary neoplastic syndrome, neurofibromatosis, familial spinal, Watson syndrome (ClinVar).

How common is NF1 p.Ser665Phe (c.1994C>T) in the general population?

NF1 p.Ser665Phe (c.1994C>T) is rare (popmax 0.665%, afr) (gnomAD).

What do computational predictors say about NF1 p.Ser665Phe (c.1994C>T)?

AlphaMissense predicts likely benign (score 0.1215) — an in-silico prediction, not a clinical call.

NF1 p.Ser665Phe

c.1994C>T · rs145891889 · VCV134881

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.1215 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.665%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1215	likely benign
REVEL	0.238	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.9, phastCons 0.99
Regional constraint	o/e 0.59	unconstrained · MANE · 7,685 bp · p 1.1e-24 · regional, not allelic
Overall
CADD	19.89	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 0.665% African / African-American · 499/74,986 alleles

Filtering AF 0.617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.598%

Overall 0.0355% 573/1,613,520 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.665%	150
Middle Eastern	0.116%	866
Remaining individualsnot grpmax-eligible	0.0496%	2,015
Admixed American	0.0383%	2,608
South Asian	0.00329%	30,359
European (non-Finnish)	0.000848%	117,962

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.Ser665Phe
Coding: c.1994C>T
MANE Select: NM_001042492
dbSNP: rs145891889
Type: single nucleotide variant
Location: chr17:31225243 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 665: a UniProt-annotated variant site (in nf1; uncertain significance)

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 neurofibromatosis type 1

Similar variants

NF1 p.Ser665= Likely benign ★★ same residue
NF1 p.Ser665Tyr Uncertain significance ★ ⚠ same residue
NF1 p.Ser665fs Pathogenic ★ 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

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-ser665phe (accessed [today's date]).

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