Is STK11 p.Ser421= (c.1263C>T) pathogenic?

STK11 p.Ser421= (c.1263C>T) is classified Conflicting classifications of pathogenicity in STK11 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-26). Very rare (popmax 0.0013%, nfe); Associated with Peutz-Jeghers syndrome.

What condition is associated with STK11 p.Ser421= (c.1263C>T)?

STK11 p.Ser421= (c.1263C>T) is associated with Peutz-Jeghers syndrome, hereditary neoplastic syndrome (ClinVar).

How common is STK11 p.Ser421= (c.1263C>T) in the general population?

STK11 p.Ser421= (c.1263C>T) is very rare (popmax 0.0013%, nfe) (gnomAD).

How is Peutz-Jeghers syndrome inherited?

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

STK11 p.Ser421=

c.1263C>T · rs1472814508 · VCV458031

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0013%, nfe)

Conditions

Peutz-Jeghers syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.2, phastCons 1
Overall
CADD	12.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0013% European (non-Finnish) · 15/1,153,522 alleles

Filtering AF 0.000781% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000619%

Overall 0.000962% 15/1,558,972 alleles · very rare exomes 11/1,406,730 · genomes 4/152,242 · 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: STK11
Protein: p.Ser421=
Coding: c.1263C>T
MANE Select: NM_000455
dbSNP: rs1472814508
Type: single nucleotide variant
Location: chr19:1226608 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 4 PDB
Residue 421: the 'disordered' region

Full STK11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Peutz-Jeghers syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Peutz-Jeghers syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

STK11 p.Ser421Arg Uncertain significance ★ ⚠ same residue
STK11 p.Ser421Ile Uncertain significance ★ ⚠ same residue
STK11 p.Ser421Gly Likely benign ★ same residue
STK11 p.Ser421Asn Uncertain significance ★★ same residue
STK11 p.Ser421Leu Conflicting classifications of pathogenicity ★ same residue
STK11 c.290+1G>A Pathogenic ★★ same condition
STK11 c.290+1G>C Pathogenic ★★ same condition
STK11 c.290+1G>T 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/stk11-p-ser421 (accessed [today's date]).

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