Is FLCN p.Pro228fs (c.679_680dup) pathogenic?

FLCN p.Pro228fs (c.679680dup) is classified Pathogenic in FLCN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). Very rare (popmax 6.2e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Pro228fs (c.679_680dup)?

FLCN p.Pro228fs (c.679_680dup) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Pro228fs (c.679_680dup) in the general population?

FLCN p.Pro228fs (c.679_680dup) is very rare (popmax 6.2e-05%) (gnomAD).

FLCN p.Pro228fs

c.679_680dup · VCV4257934

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -20	GERP -3.3
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,074 alleles · very rare exomes 0/1,461,888 · genomes 1/152,186 · 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.Pro228fs
Coding: c.679_680dup
MANE Select: NM_144997
Type: Duplication
Location: chr17:17222599 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 228: the udenn 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

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

Similar variants

FLCN p.Pro228Ser Uncertain significance ★★ ⚠ same residue
FLCN p.Pro228Arg Uncertain significance ★ ⚠ same residue
FLCN p.Ala541fs Pathogenic/Likely pathogenic ★★ same condition
FLCN p.Ala67fs Pathogenic ★★ same condition
FLCN p.Asp476fs Pathogenic ★★ same condition
FLCN p.Gly319fs Pathogenic ★★ same condition
FLCN p.Ile402fs Pathogenic ★★ same condition
FLCN p.Leu117fs 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-pro228fs (accessed [today's date]).

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