Is FLCN p.Pro528Arg (c.1583C>G) pathogenic?

FLCN p.Pro528Arg (c.1583C>G) is classified Uncertain significance in FLCN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-18). AlphaMissense: ambiguous (0.4158); Absent from gnomAD v4.1; Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Pro528Arg (c.1583C>G)?

FLCN p.Pro528Arg (c.1583C>G) is associated with Birt-Hogg-Dube syndrome (ClinVar).

How common is FLCN p.Pro528Arg (c.1583C>G) in the general population?

FLCN p.Pro528Arg (c.1583C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FLCN p.Pro528Arg (c.1583C>G)?

AlphaMissense predicts ambiguous (score 0.4158) — an in-silico prediction, not a clinical call.

FLCN p.Pro528Arg

c.1583C>G · VCV3672775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4158 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Birt-Hogg-Dube syndrome

Computational evidence

Protein change
AlphaMissense	0.4158	ambiguous
REVEL	0.463	indeterminate
SaProt	LLR -8.37	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLCN
Protein: p.Pro528Arg
Coding: c.1583C>G
MANE Select: NM_144997
Type: single nucleotide variant
Location: chr17:17213812 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 528: a UniProt-annotated variant site (in psp); a UniProt-annotated variant site (in bhd1); the ddenn flcn/smcr8-type domain

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.Pro528Leu Uncertain significance ★★ ⚠ same residue
FLCN p.Pro528Ser Uncertain significance ★★ ⚠ same residue
FLCN p.Pro528= 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-pro528arg (accessed [today's date]).

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