Is FLCN p.Asp198= (c.594T>C) pathogenic?

FLCN p.Asp198= (c.594T>C) is classified Likely benign in FLCN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-11). Very rare (popmax 0.0011%, sas); Associated with Birt-Hogg-Dube syndrome.

What condition is associated with FLCN p.Asp198= (c.594T>C)?

FLCN p.Asp198= (c.594T>C) is associated with Birt-Hogg-Dube syndrome, hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Asp198= (c.594T>C) in the general population?

FLCN p.Asp198= (c.594T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

FLCN p.Asp198=

c.594T>C · rs2144971951 · VCV2146386

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Birt-Hogg-Dube syndrome

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 -2	GERP -2.2
Overall
CADD	4.119	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Overall 0.000124% 2/1,613,400 alleles · very rare exomes 2/1,461,042 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,022

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.Asp198=
Coding: c.594T>C
MANE Select: NM_144997
dbSNP: rs2144971951
Type: single nucleotide variant
Location: chr17:17223946 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 198: the udenn flcn/smcr8-type domain; a UniProt-annotated variant site (in psp); an α-helix

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

Similar variants

FLCN p.Asp198Tyr Uncertain significance ★★ ⚠ same residue
FLCN p.Asp198Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
FLCN p.Asp198Gly Uncertain significance ★ ⚠ same residue
FLCN p.Asp198Val Uncertain significance ★ ⚠ same residue
FLCN p.Asp198del Uncertain significance ★★ 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-asp198 (accessed [today's date]).

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