Is FLCN p.Pro63His (c.188C>A) pathogenic?

FLCN p.Pro63His (c.188C>A) is classified Uncertain significance in FLCN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-20). AlphaMissense: likely benign (0.1026); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Pro63His (c.188C>A)?

FLCN p.Pro63His (c.188C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FLCN p.Pro63His (c.188C>A) in the general population?

FLCN p.Pro63His (c.188C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FLCN p.Pro63His (c.188C>A)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

FLCN p.Pro63His

c.188C>A · rs2145042161 · VCV1782036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.314	indeterminate
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Pro63His
Coding: c.188C>A
MANE Select: NM_144997
dbSNP: rs2145042161
Type: single nucleotide variant
Location: chr17:17227950 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 63: the 'disordered' region

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.Pro63= Likely benign ★★ same residue
FLCN p.Pro63Ala Uncertain significance ★ ⚠ same residue
FLCN p.Pro63Ser 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-pro63his (accessed [today's date]).

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