Is STK11 p.Pro321= (c.963C>T) pathogenic?

STK11 p.Pro321= (c.963C>T) is classified Benign/Likely benign in STK11 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-27). Very rare (popmax 0.00269%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with STK11 p.Pro321= (c.963C>T)?

STK11 p.Pro321= (c.963C>T) is associated with hereditary neoplastic syndrome, Peutz-Jeghers syndrome (ClinVar).

How common is STK11 p.Pro321= (c.963C>T) in the general population?

STK11 p.Pro321= (c.963C>T) is very rare (popmax 0.00269%, afr) (gnomAD).

STK11 p.Pro321=

c.963C>T · rs878853993 · VCV237808

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Conditions

hereditary neoplastic 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 -0.008	GERP -0.19, phastCons 0.76
Overall
CADD	6.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00269% African / African-American · 2/74,396 alleles

Filtering AF 0.000446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.00044% 7/1,590,016 alleles · very rare exomes 6/1,437,918 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,198
European (non-Finnish)	0.000428%	233,816

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.Pro321=
Coding: c.963C>T
MANE Select: NM_000455
dbSNP: rs878853993
Type: single nucleotide variant
Location: chr19:1223027 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 4 PDB
Residue 321: an α-helix; the 'disordered' region

Full STK11 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: Peutz-Jeghers syndrome

Similar variants

STK11 p.Pro321Ala Uncertain significance ★★ ⚠ same residue
STK11 p.Pro321Thr Uncertain significance ★ ⚠ same residue
STK11 p.Pro321fs Pathogenic ★ 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
STK11 c.290+2T>A Pathogenic/Likely pathogenic ★★ same condition
STK11 c.291-1G>A 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-pro321 (accessed [today's date]).

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