Is FLCN p.Phe142Ile (c.424T>A) pathogenic?

FLCN p.Phe142Ile (c.424T>A) is classified Uncertain significance in FLCN (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-05). AlphaMissense: likely pathogenic (0.9135); Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Phe142Ile (c.424T>A)?

FLCN p.Phe142Ile (c.424T>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Phe142Ile (c.424T>A) in the general population?

FLCN p.Phe142Ile (c.424T>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about FLCN p.Phe142Ile (c.424T>A)?

AlphaMissense predicts likely pathogenic (score 0.9135) — an in-silico prediction, not a clinical call.

FLCN p.Phe142Ile

c.424T>A · rs2047181001 · VCV1739081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9135	likely pathogenic
REVEL	0.471	indeterminate
SaProt	LLR -5.41	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 0.66, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	24.3	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 0.0165% Middle Eastern · 1/6,064 alleles

Overall 0.000125% 2/1,604,422 alleles · ultra-rare exomes 1/1,452,168 · genomes 1/152,254 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,064
European (non-Finnish)	8.51e-05%	1,175,478

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.Phe142Ile
Coding: c.424T>A
MANE Select: NM_144997
dbSNP: rs2047181001
Type: single nucleotide variant
Location: chr17:17224116 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 142: the udenn flcn/smcr8-type domain; 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

Similar variants

FLCN p.Phe142Cys Uncertain significance ★ ⚠ same residue
FLCN p.Phe142Tyr Uncertain significance ★ ⚠ same residue
FLCN c.1062+1G>A Pathogenic ★★ same condition
FLCN c.1062+2T>G Pathogenic ★★ same condition
FLCN c.1063-2A>G Pathogenic/Likely pathogenic ★★ same condition
FLCN c.1176+1G>A Likely pathogenic ★★ same condition
FLCN c.1176+1G>C Pathogenic/Likely pathogenic ★★ same condition
FLCN c.1176+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-phe142ile (accessed [today's date]).

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