Is FLCN p.Asp33Glu (c.99T>A) pathogenic?

FLCN p.Asp33Glu (c.99T>A) is classified Conflicting classifications of pathogenicity in FLCN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-09). AlphaMissense: likely benign (0.0852); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with FLCN p.Asp33Glu (c.99T>A)?

FLCN p.Asp33Glu (c.99T>A) is associated with hereditary neoplastic syndrome, colorectal cancer, nonpapillary renal cell carcinoma (ClinVar).

How common is FLCN p.Asp33Glu (c.99T>A) in the general population?

FLCN p.Asp33Glu (c.99T>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about FLCN p.Asp33Glu (c.99T>A)?

AlphaMissense predicts likely benign (score 0.0852) — an in-silico prediction, not a clinical call.

FLCN p.Asp33Glu

c.99T>A · rs375348725 · VCV659702

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0852 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0852	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.4	GERP -3.1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	0.002	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 0.00133% African / African-American · 1/74,924 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,680 alleles · very rare exomes 6/1,461,522 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,924
European (non-Finnish)	0.000593%	168,577

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.Asp33Glu
Coding: c.99T>A
MANE Select: NM_144997
dbSNP: rs375348725
Type: single nucleotide variant
Location: chr17:17228039 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.14 · 4 PDB
Residue 33: 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

Also linked: colorectal cancer nonpapillary renal cell carcinoma familial spontaneous pneumothorax Birt-Hogg-Dube syndrome Birt-Hogg-Dube syndrome 1

Similar variants

FLCN p.Asp33Tyr Uncertain significance ★★ ⚠ same residue
FLCN p.Asp33His Benign/Likely benign ★★ same residue
FLCN p.Asp33Asn Uncertain significance ★ ⚠ same residue
FLCN p.Asp33= Likely benign ★ same residue
FLCN p.Asp33fs Pathogenic ★ same residue
FLCN p.Asp33Gly Uncertain significance ⚠ same residue
FLCN c.1062+1G>A Pathogenic ★★ same condition
FLCN c.1062+2T>G 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-asp33glu (accessed [today's date]).

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