Is FLCN p.Ile172Phe (c.514A>T) pathogenic?

FLCN p.Ile172Phe (c.514A>T) is classified Uncertain significance in FLCN (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-14). AlphaMissense: ambiguous (0.4438); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Ile172Phe (c.514A>T)?

FLCN p.Ile172Phe (c.514A>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Ile172Phe (c.514A>T) in the general population?

FLCN p.Ile172Phe (c.514A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FLCN p.Ile172Phe (c.514A>T)?

AlphaMissense predicts ambiguous (score 0.4438) — an in-silico prediction, not a clinical call.

FLCN p.Ile172Phe

c.514A>T · VCV4871390

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4438 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4438	ambiguous
REVEL	0.654	pathogenic-leaning
SaProt	LLR -8.53	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -0.35, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	22.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLCN
Protein: p.Ile172Phe
Coding: c.514A>T
MANE Select: NM_144997
Type: single nucleotide variant
Location: chr17:17224026 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 172: the udenn flcn/smcr8-type domain; a UniProt-annotated variant site (in psp); 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.Ile172Val Uncertain significance ★★ ⚠ same residue
FLCN p.Ile172= Conflicting classifications of pathogenicity ★ same residue
FLCN p.Ile172Ser 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

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-ile172phe (accessed [today's date]).

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