Is FLCN p.Ser577Pro (c.1729T>C) pathogenic?

FLCN p.Ser577Pro (c.1729T>C) is classified Conflicting classifications of pathogenicity in FLCN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-03-26). AlphaMissense: likely benign (0.0518); Very rare (popmax 0.00223%, eas); Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Ser577Pro (c.1729T>C)?

FLCN p.Ser577Pro (c.1729T>C) is associated with Birt-Hogg-Dube syndrome, hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Ser577Pro (c.1729T>C) in the general population?

FLCN p.Ser577Pro (c.1729T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FLCN p.Ser577Pro (c.1729T>C)?

AlphaMissense predicts likely benign (score 0.0518) — an in-silico prediction, not a clinical call.

FLCN p.Ser577Pro

c.1729T>C · rs886426221 · VCV1425769

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Birt-Hogg-Dube syndrome

Computational evidence

Protein change
AlphaMissense	0.0518	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -6.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -3.4, phastCons 0.97
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	14.19	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

Grpmax group 0.00223% East Asian · 1/44,874 alleles

Overall 0.000124% 2/1,613,812 alleles · very rare exomes 2/1,461,864 · genomes 0/151,948 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
European (non-Finnish)	8.47e-05%	1,179,976

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.Ser577Pro
Coding: c.1729T>C
MANE Select: NM_144997
dbSNP: rs886426221
Type: single nucleotide variant
Location: chr17:17213666 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 577: a UniProt-annotated variant site (in psp); a UniProt-annotated variant site (in bhd1)

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

Similar variants

FLCN p.Ser577Ala Uncertain significance ★★ ⚠ same residue
FLCN p.Ser577Phe Uncertain significance ★★ ⚠ same residue
FLCN p.Ser577Cys Uncertain significance ★ ⚠ same residue
FLCN p.Ser577fs Uncertain significance ★ 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

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-ser577pro (accessed [today's date]).

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