Is FLCN p.Pro428= (c.1284C>T) pathogenic?

FLCN p.Pro428= (c.1284C>T) is classified Benign/Likely benign in FLCN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-24). Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Pro428= (c.1284C>T)?

FLCN p.Pro428= (c.1284C>T) is associated with hereditary neoplastic syndrome, Birt-Hogg-Dube syndrome, Birt-Hogg-Dube syndrome 1 (ClinVar).

How common is FLCN p.Pro428= (c.1284C>T) in the general population?

FLCN p.Pro428= (c.1284C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

FLCN p.Pro428=

c.1284C>T · rs942763423 · VCV1098103

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

hereditary neoplastic 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 0.15	GERP -2.8, phastCons 0.76
Overall
CADD	7.518	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,718 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,590 alleles · very rare exomes 4/1,461,290 · genomes 0/152,300 · 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.Pro428=
Coding: c.1284C>T
MANE Select: NM_144997
dbSNP: rs942763423
Type: single nucleotide variant
Location: chr17:17216396 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 428: 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

FLCN p.Pro428Thr Uncertain significance ★★ ⚠ same residue
FLCN p.Pro428Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Pro428Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Pro428His Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Pro428Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Pro428Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN c.1062+1G>A Pathogenic ★★ same condition
FLCN c.1062+2T>G 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-pro428 (accessed [today's date]).

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