Is FLCN p.Ala45= (c.135G>A) pathogenic?

FLCN p.Ala45= (c.135G>A) is classified Conflicting classifications of pathogenicity in FLCN (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-09). Ultra-rare (popmax 0.0165%, mid); Associated with Birt-Hogg-Dube syndrome 1.

What condition is associated with FLCN p.Ala45= (c.135G>A)?

FLCN p.Ala45= (c.135G>A) is associated with Birt-Hogg-Dube syndrome 1, familial spontaneous pneumothorax, hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Ala45= (c.135G>A) in the general population?

FLCN p.Ala45= (c.135G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

FLCN p.Ala45=

c.135G>A · rs759930161 · VCV184633

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Birt-Hogg-Dube syndrome 1

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 -14	GERP -3.1
Overall
CADD	0.203	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00217% 35/1,614,058 alleles · ultra-rare exomes 33/1,461,686 · genomes 2/152,372 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.004%	25,023
European (non-Finnish)	0.00254%	39,335
East Asian	0.00223%	44,886

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.Ala45=
Coding: c.135G>A
MANE Select: NM_144997
dbSNP: rs759930161
Type: single nucleotide variant
Location: chr17:17228003 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 45: the 'disordered' region

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

Disease context

Birt-Hogg-Dube syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial spontaneous pneumothorax hereditary neoplastic syndrome Birt-Hogg-Dube syndrome

Similar variants

FLCN p.Ala45Glu Uncertain significance ★★ ⚠ same residue
FLCN p.Ala45Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Ala45Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala45 (accessed [today's date]).

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