Is FLCN p.Leu289= (c.867C>T) pathogenic?

FLCN p.Leu289= (c.867C>T) is classified Benign/Likely benign in FLCN (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0294%, afr); Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Leu289= (c.867C>T)?

FLCN p.Leu289= (c.867C>T) is associated with Birt-Hogg-Dube syndrome, colorectal cancer, nonpapillary renal cell carcinoma (ClinVar).

How common is FLCN p.Leu289= (c.867C>T) in the general population?

FLCN p.Leu289= (c.867C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

FLCN p.Leu289=

c.867C>T · rs367562964 · VCV460636

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Conditions

Birt-Hogg-Dube syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.6	GERP -3.9
Overall
CADD	0.556	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0294% African / African-American · 22/74,886 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.0031% 50/1,613,122 alleles · ultra-rare exomes 40/1,461,016 · genomes 10/152,106 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,404
Remaining individualsnot grpmax-eligible	0.0064%	15,620
East Asian	0.00223%	44,894
European (non-Finnish)	0.00195%	51,305

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: FLCN
Protein: p.Leu289=
Coding: c.867C>T
MANE Select: NM_144997
dbSNP: rs367562964
Type: single nucleotide variant
Location: chr17:17221541 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 289: a UniProt-annotated variant site (in psp); a UniProt-annotated variant site (in bhd1); an α-helix

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

Disease context

Birt-Hogg-Dube syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer nonpapillary renal cell carcinoma familial spontaneous pneumothorax Potocki-Lupski syndrome hereditary neoplastic syndrome Birt-Hogg-Dube syndrome 1

Similar variants

FLCN p.Leu289Phe Uncertain significance ★ ⚠ same residue
FLCN p.Leu289Val Uncertain significance ★ ⚠ same residue
FLCN c.1062+1G>A Pathogenic ★★ same condition
FLCN c.1062+2T>G Pathogenic ★★ same condition
FLCN c.1063-1G>T Likely pathogenic ★★ same condition
FLCN c.1063-2A>G Pathogenic/Likely pathogenic ★★ same condition
FLCN c.1176+1G>A Likely pathogenic ★★ same condition
FLCN c.1176+1G>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/flcn-p-leu289 (accessed [today's date]).

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