Is FLCN p.Pro427= (c.1281C>G) pathogenic?

FLCN p.Pro427= (c.1281C>G) is classified Conflicting classifications of pathogenicity in FLCN (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-01). Rare (popmax 0.48%, mid); Associated with Birt-Hogg-Dube syndrome 1.

What condition is associated with FLCN p.Pro427= (c.1281C>G)?

FLCN p.Pro427= (c.1281C>G) is associated with Birt-Hogg-Dube syndrome 1, familial spontaneous pneumothorax, hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Pro427= (c.1281C>G) in the general population?

FLCN p.Pro427= (c.1281C>G) is rare (popmax 0.48%, mid) (gnomAD).

FLCN p.Pro427=

c.1281C>G · rs372207262 · VCV322064

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.48%, 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 -1.6	GERP -3.8
Overall
CADD	2.474	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.48% Middle Eastern · 29/6,046 alleles

Filtering AF 0.343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.297%

Overall 0.0121% 196/1,613,622 alleles · rare exomes 171/1,461,308 · genomes 25/152,314 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.48%	208
Ashkenazi Jewishnot grpmax-eligible	0.199%	501
Remaining individualsnot grpmax-eligible	0.0256%	3,905
Admixed American	0.0117%	8,570
European (non-Finnish)	0.00704%	14,214
African / African-American	0.00133%	75,050
South Asian	0.0011%	91,058

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.Pro427=
Coding: c.1281C>G
MANE Select: NM_144997
dbSNP: rs372207262
Type: single nucleotide variant
Location: chr17:17216399 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 427: the cdenn flcn/smcr8-type domain; 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 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.Pro427Arg Uncertain significance ★★ ⚠ same residue
FLCN p.Pro427Leu Uncertain significance ★★ ⚠ same residue
FLCN p.Pro427Thr Uncertain significance ★★ ⚠ same residue
FLCN p.Pro427Ala Uncertain significance ★ ⚠ same residue
FLCN p.Pro427His 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

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-pro427 (accessed [today's date]).

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