Is FLCN p.Pro451= (c.1353T>C) pathogenic?

FLCN p.Pro451= (c.1353T>C) is classified Benign/Likely benign in FLCN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-24). Very rare (popmax 0.00133%, afr); Associated with Birt-Hogg-Dube syndrome 1.

What condition is associated with FLCN p.Pro451= (c.1353T>C)?

FLCN p.Pro451= (c.1353T>C) is associated with Birt-Hogg-Dube syndrome 1, colorectal cancer, nonpapillary renal cell carcinoma (ClinVar).

How common is FLCN p.Pro451= (c.1353T>C) in the general population?

FLCN p.Pro451= (c.1353T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

FLCN p.Pro451=

c.1353T>C · rs1597580172 · VCV707712

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Birt-Hogg-Dube syndrome 1

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 -12	GERP -3.6
Overall
CADD	0.057	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,066 alleles

Overall 0.000124% 2/1,614,124 alleles · very rare exomes 2/1,461,814 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
African / African-Americangrpmax	0.00133%	75,066

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro451=
Coding: c.1353T>C
MANE Select: NM_144997
dbSNP: rs1597580172
Type: single nucleotide variant
Location: chr17:17215264 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 451: the cdenn flcn/smcr8-type domain; 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 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

FLCN p.Pro451Arg Uncertain significance ★★ ⚠ same residue
FLCN p.Pro451Ser Uncertain significance ★★ ⚠ same residue
FLCN p.Pro451Leu Uncertain significance ★ ⚠ same residue
FLCN p.Pro451fs Pathogenic ★ 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-pro451 (accessed [today's date]).

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