Is FLCN p.Pro39Ser (c.115C>T) pathogenic?

FLCN p.Pro39Ser (c.115C>T) is classified Uncertain significance in FLCN (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-31). AlphaMissense: likely benign (0.068); Very rare (popmax 8.47e-05%, nfe); Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Pro39Ser (c.115C>T)?

FLCN p.Pro39Ser (c.115C>T) is associated with Birt-Hogg-Dube syndrome (ClinVar).

How common is FLCN p.Pro39Ser (c.115C>T) in the general population?

FLCN p.Pro39Ser (c.115C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FLCN p.Pro39Ser (c.115C>T)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

FLCN p.Pro39Ser

c.115C>T · rs1060502375 · VCV1422865

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Birt-Hogg-Dube syndrome

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.21	GERP -0.54, phastCons 0.52
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	9.929	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 8.47e-05% European (non-Finnish) · 1/1,180,056 alleles

Overall 6.2e-05% 1/1,613,940 alleles · very rare exomes 1/1,461,580 · genomes 0/152,360 · 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: FLCN
Protein: p.Pro39Ser
Coding: c.115C>T
MANE Select: NM_144997
dbSNP: rs1060502375
Type: single nucleotide variant
Location: chr17:17228023 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 39: the 'disordered' region

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

Similar variants

FLCN p.Pro39Arg Uncertain significance ★★ ⚠ same residue
FLCN p.Pro39Thr Uncertain significance ★★ ⚠ same residue
FLCN p.Pro39= Benign/Likely benign ★★ 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

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-pro39ser (accessed [today's date]).

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