Is STK11 p.Arg415Pro (c.1244G>C) pathogenic?

STK11 p.Arg415Pro (c.1244G>C) is classified Uncertain significance in STK11 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-06). AlphaMissense: likely benign (0.2201); Very rare (popmax 0.00117%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with STK11 p.Arg415Pro (c.1244G>C)?

STK11 p.Arg415Pro (c.1244G>C) is associated with hereditary neoplastic syndrome, Peutz-Jeghers syndrome (ClinVar).

How common is STK11 p.Arg415Pro (c.1244G>C) in the general population?

STK11 p.Arg415Pro (c.1244G>C) is very rare (popmax 0.00117%, sas) (gnomAD).

What do computational predictors say about STK11 p.Arg415Pro (c.1244G>C)?

AlphaMissense predicts likely benign (score 0.2201) — an in-silico prediction, not a clinical call.

STK11 p.Arg415Pro

c.1244G>C · rs775978755 · VCV480710

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00117%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2201	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 4,642 bp · p 0.03 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00117% South Asian · 1/85,768 alleles

Overall 7.05e-05% 1/1,419,070 alleles · very rare

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.Arg415Pro
Coding: c.1244G>C
MANE Select: NM_000455
dbSNP: rs775978755
Type: single nucleotide variant
Location: chr19:1226589 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 4 PDB
Residue 415: 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.Arg415Leu Uncertain significance ★★ ⚠ same residue
STK11 p.Arg415Ser Uncertain significance ★★ ⚠ same residue
STK11 p.Arg415= Benign/Likely benign ★★ same residue
STK11 p.Arg415Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
STK11 p.Arg415Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
STK11 p.Arg415His Conflicting classifications of pathogenicity ★ ⚠ same residue
STK11 p.Arg415fs Uncertain significance ★ same residue
STK11 c.290+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-arg415pro (accessed [today's date]).

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