Is FLCN p.Ile438= (c.1314C>A) pathogenic?

FLCN p.Ile438= (c.1314C>A) is classified Benign/Likely benign in FLCN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). Very rare (popmax 0.00549%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Ile438= (c.1314C>A)?

FLCN p.Ile438= (c.1314C>A) is associated with hereditary neoplastic syndrome, Birt-Hogg-Dube syndrome (ClinVar).

How common is FLCN p.Ile438= (c.1314C>A) in the general population?

FLCN p.Ile438= (c.1314C>A) is very rare (popmax 0.00549%, sas) (gnomAD).

FLCN p.Ile438=

c.1314C>A · rs771247255 · VCV2160867

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -9	GERP -3.6
Overall
CADD	1.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,074 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000372% 6/1,614,010 alleles · very rare exomes 6/1,461,748 · genomes 0/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,215
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Ile438=
Coding: c.1314C>A
MANE Select: NM_144997
dbSNP: rs771247255
Type: single nucleotide variant
Location: chr17:17215303 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 438: the cdenn flcn/smcr8-type domain; a UniProt-annotated variant site (in psp); a UniProt-annotated variant site (in bhd1); a β-strand

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

Also linked: Birt-Hogg-Dube syndrome

Similar variants

FLCN p.Ile438Leu Uncertain significance ★ ⚠ same residue
FLCN p.Ile438Met Uncertain significance ★ ⚠ same residue
FLCN p.Ile438Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Ile438Thr Uncertain significance ★ ⚠ same residue
FLCN p.Ile438Val Likely benign ★ 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

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-ile438 (accessed [today's date]).

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