Is FLCN p.Ser330= (c.990C>G) pathogenic?

FLCN p.Ser330= (c.990C>G) is classified Benign/Likely benign in FLCN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-21). Very rare (popmax 0.000169%, nfe); Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Ser330= (c.990C>G)?

FLCN p.Ser330= (c.990C>G) is associated with Birt-Hogg-Dube syndrome, hereditary neoplastic syndrome, Birt-Hogg-Dube syndrome 1 (ClinVar).

How common is FLCN p.Ser330= (c.990C>G) in the general population?

FLCN p.Ser330= (c.990C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

FLCN p.Ser330=

c.990C>G · VCV3677048

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 2	GERP 0.94, phastCons 0.99
Overall
CADD	5.842	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,152 alleles · very rare exomes 2/1,461,828 · genomes 0/152,324 · 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.Ser330=
Coding: c.990C>G
MANE Select: NM_144997
Type: single nucleotide variant
Location: chr17:17219091 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 330: a UniProt-annotated variant site (in psp); a UniProt-annotated variant site (in bhd1); 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

Also linked: hereditary neoplastic syndrome Birt-Hogg-Dube syndrome 1

Similar variants

FLCN p.Ser330Phe Uncertain significance ★★ ⚠ same residue
FLCN p.Ser330fs Pathogenic ★ 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-ser330 (accessed [today's date]).

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