Is FLCN p.Ser496Phe (c.1487C>T) pathogenic?

FLCN p.Ser496Phe (c.1487C>T) is classified Uncertain significance in FLCN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.8076); Very rare (popmax 0.00446%, eas); Associated with familial spontaneous pneumothorax.

What condition is associated with FLCN p.Ser496Phe (c.1487C>T)?

FLCN p.Ser496Phe (c.1487C>T) is associated with familial spontaneous pneumothorax, colorectal cancer, nonpapillary renal cell carcinoma (ClinVar).

How common is FLCN p.Ser496Phe (c.1487C>T) in the general population?

FLCN p.Ser496Phe (c.1487C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Familial spontaneous pneumothorax inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLCN p.Ser496Phe (c.1487C>T)?

AlphaMissense predicts likely pathogenic (score 0.8076) — an in-silico prediction, not a clinical call.

FLCN p.Ser496Phe

c.1487C>T · rs750535468 · VCV1011594

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial spontaneous pneumothorax

Computational evidence

Protein change
AlphaMissense	0.8076	likely pathogenic
REVEL	0.759	pathogenic-leaning
SaProt	LLR -11.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,218 alleles · very rare exomes 2/1,461,882 · genomes 0/152,336 · 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.Ser496Phe
Coding: c.1487C>T
MANE Select: NM_144997
dbSNP: rs750535468
Type: single nucleotide variant
Location: chr17:17215036 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 496: 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

familial spontaneous pneumothorax — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer nonpapillary renal cell carcinoma Potocki-Lupski syndrome hereditary neoplastic syndrome Birt-Hogg-Dube syndrome

For Familial spontaneous pneumothorax (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: 1-5 / 10 000 (Finland)

Similar variants

FLCN p.Ser496Ala Uncertain significance ★ ⚠ same residue
FLCN p.Ser496Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Ser496Pro Uncertain significance ★ ⚠ same residue
FLCN p.Ser496Tyr Uncertain significance ★ ⚠ same residue
FLCN p.Ser496= Likely benign ★ same residue
FLCN p.Ser496fs 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-ser496phe (accessed [today's date]).

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