Is FLCN p.Val400Phe (c.1198G>T) pathogenic?

FLCN p.Val400Phe (c.1198G>T) is classified Conflicting classifications of pathogenicity in FLCN (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: ambiguous (0.4715); Very rare (popmax 0.00136%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Val400Phe (c.1198G>T)?

FLCN p.Val400Phe (c.1198G>T) is associated with hereditary neoplastic syndrome, Birt-Hogg-Dube syndrome (ClinVar).

How common is FLCN p.Val400Phe (c.1198G>T) in the general population?

FLCN p.Val400Phe (c.1198G>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about FLCN p.Val400Phe (c.1198G>T)?

AlphaMissense predicts ambiguous (score 0.4715) — an in-silico prediction, not a clinical call.

FLCN p.Val400Phe

c.1198G>T · rs148257120 · VCV96472

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4715 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4715	ambiguous
REVEL	0.596	indeterminate
SaProt	LLR -8.85	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,906 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,613,690 alleles · very rare exomes 16/1,461,570 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)grpmax	0.00136%	73,744

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.Val400Phe
Coding: c.1198G>T
MANE Select: NM_144997
dbSNP: rs148257120
Type: single nucleotide variant
Location: chr17:17216482 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 400: 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

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

Also linked: Birt-Hogg-Dube syndrome

Similar variants

FLCN p.Val400Ile Likely benign ★★ same residue
FLCN p.Val400Ala Conflicting classifications of pathogenicity ★ same residue
FLCN p.Val400Leu 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
FLCN c.1063-2A>G Pathogenic/Likely pathogenic ★★ same condition
FLCN c.1176+1G>A 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-val400phe (accessed [today's date]).

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