Is NF1 p.Ser421Phe (c.1262C>T) pathogenic?

NF1 p.Ser421Phe (c.1262C>T) is classified Uncertain significance in NF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). AlphaMissense: likely pathogenic (0.6719); Very rare (popmax 0.00134%, afr); Associated with neurofibromatosis type 1.

What condition is associated with NF1 p.Ser421Phe (c.1262C>T)?

NF1 p.Ser421Phe (c.1262C>T) is associated with neurofibromatosis type 1, hereditary neoplastic syndrome (ClinVar).

How common is NF1 p.Ser421Phe (c.1262C>T) in the general population?

NF1 p.Ser421Phe (c.1262C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Neurofibromatosis type 1 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NF1 p.Ser421Phe (c.1262C>T)?

AlphaMissense predicts likely pathogenic (score 0.6719) — an in-silico prediction, not a clinical call.

NF1 p.Ser421Phe

c.1262C>T · rs1353527088 · VCV1927014

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

neurofibromatosis type 1

Computational evidence

Protein change
AlphaMissense	0.6719	likely pathogenic
REVEL	0.486	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 41 kb · p 4.2e-25 · regional, not allelic
Overall
CADD	25.9	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 0.00134% African / African-American · 1/74,896 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,540 alleles · very rare exomes 2/1,461,370 · genomes 1/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,896
European (non-Finnish)	0.00017%	589,838

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.Ser421Phe
Coding: c.1262C>T
MANE Select: NM_001042492
dbSNP: rs1353527088
Type: single nucleotide variant
Location: chr17:31206241 (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

neurofibromatosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Neurofibromatosis type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-5 / 10 000 (United Kingdom)

Similar variants

NF1 p.Ser421= Benign/Likely benign ★★ same residue
NF1 p.Ser421Ala Conflicting classifications of pathogenicity ★ same residue
NF1 p.Ser421Thr Uncertain significance ★ same residue
NF1 p.Ser421fs 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

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-ser421phe (accessed [today's date]).

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