Is FLCN p.Ser331Phe (c.992C>T) pathogenic?

FLCN p.Ser331Phe (c.992C>T) is classified Conflicting classifications of pathogenicity in FLCN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0724); Ultra-rare (popmax 0.0401%, eas); Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Ser331Phe (c.992C>T)?

FLCN p.Ser331Phe (c.992C>T) is associated with Birt-Hogg-Dube syndrome, hereditary neoplastic syndrome, Birt-Hogg-Dube syndrome 1 (ClinVar).

How common is FLCN p.Ser331Phe (c.992C>T) in the general population?

FLCN p.Ser331Phe (c.992C>T) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about FLCN p.Ser331Phe (c.992C>T)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

FLCN p.Ser331Phe

c.992C>T · rs202215080 · VCV823563

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Birt-Hogg-Dube syndrome

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -9.05	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 0.5	GERP -3.9
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	3.699	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 0.0401% East Asian · 18/44,882 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00149% 24/1,614,168 alleles · ultra-rare exomes 17/1,461,826 · genomes 7/152,342 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,493
Remaining individualsnot grpmax-eligible	0.0016%	62,512
Finnishnot grpmax-eligible	0.00156%	63,990
European (non-Finnish)	0.000339%	295,009

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.Ser331Phe
Coding: c.992C>T
MANE Select: NM_144997
dbSNP: rs202215080
Type: single nucleotide variant
Location: chr17:17219089 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 331: 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.Ser331Pro Uncertain significance ★★ ⚠ same residue
FLCN p.Ser331= Benign/Likely benign ★★ same residue
FLCN p.Ser331Cys Uncertain significance ★ ⚠ same residue
FLCN p.Ser331Tyr Uncertain significance ★ ⚠ same residue
FLCN p.Ser331del Uncertain significance ★★ same residue
FLCN p.Ser331fs Pathogenic 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-ser331phe (accessed [today's date]).

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