Is NF1 p.Ser421= (c.1263C>T) pathogenic?

NF1 p.Ser421= (c.1263C>T) is classified Benign/Likely benign in NF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-15). Very rare (popmax 0.00659%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with NF1 p.Ser421= (c.1263C>T)?

NF1 p.Ser421= (c.1263C>T) is associated with hereditary neoplastic syndrome, neurofibromatosis type 1 (ClinVar).

How common is NF1 p.Ser421= (c.1263C>T) in the general population?

NF1 p.Ser421= (c.1263C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

NF1 p.Ser421=

c.1263C>T · rs767410768 · VCV232136

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

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	all four deltas below 0.2 · C>A here scores Δ0.56 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.085	GERP -3.6, phastCons 0.98
Overall
CADD	7.184	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,062 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00112% 18/1,613,404 alleles · very rare exomes 16/1,461,360 · genomes 2/152,044 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,177
East Asian	0.00446%	22,439
Remaining individualsnot grpmax-eligible	0.0032%	31,222
Admixed American	0.00167%	59,964
African / African-American	0.00134%	74,860
European (non-Finnish)	0.000509%	196,607

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.Ser421=
Coding: c.1263C>T
MANE Select: NM_001042492
dbSNP: rs767410768
Type: single nucleotide variant
Location: chr17:31206242 (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.Ser421Phe Uncertain significance ★★ 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-ser421 (accessed [today's date]).

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