Is FLCN p.Ala445Ser (c.1333G>T) pathogenic?

FLCN p.Ala445Ser (c.1333G>T) is classified Uncertain significance in FLCN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-07). AlphaMissense: likely benign (0.0686); Very rare (popmax 0.00133%, afr); Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Ala445Ser (c.1333G>T)?

FLCN p.Ala445Ser (c.1333G>T) is associated with Birt-Hogg-Dube syndrome, hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Ala445Ser (c.1333G>T) in the general population?

FLCN p.Ala445Ser (c.1333G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about FLCN p.Ala445Ser (c.1333G>T)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

FLCN p.Ala445Ser

c.1333G>T · rs41419545 · VCV818969

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Birt-Hogg-Dube syndrome

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.3	GERP -3.6
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	0.014	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,046 alleles

Overall 6.2e-05% 1/1,614,082 alleles · very rare exomes 1/1,461,806 · genomes 0/152,276 · 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.Ala445Ser
Coding: c.1333G>T
MANE Select: NM_144997
dbSNP: rs41419545
Type: single nucleotide variant
Location: chr17:17215284 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 445: the cdenn flcn/smcr8-type domain; a UniProt-annotated variant site (in psp); a UniProt-annotated variant site (in bhd1); a UniProt-annotated variant site (in a sporadic colorectal carcinoma; somatic mutation)

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.Ala445Gly Uncertain significance ★★ ⚠ same residue
FLCN p.Ala445Val Uncertain significance ★★ ⚠ same residue
FLCN p.Ala445Pro Uncertain significance ★ ⚠ same residue
FLCN p.Ala445Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Ala445fs Pathogenic ★ same residue
FLCN p.Ala445= Benign ★ 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-ala445ser (accessed [today's date]).

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