# NM_144997.7(FLCN):c.989_990dup (p.Ser331fs)

https://sugi.bio/variant/flcn-p-ser331fs

## Summary

**FLCN p.Ser331fs (c.989_990dup)** is classified **Pathogenic** in FLCN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-07-01). No gnomAD frequency available for this variant; Associated with Birt-Hogg-Dube syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2544194629 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FLCN gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Birt-Hogg-Dube syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0028061/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FLCN](https://sugi.bio/atlas/gene/FLCN/) |
| Protein change (HGVS p.) | p.Ser331fs |
| Coding change (HGVS c.) | c.989_990dup |
| MANE Select transcript | [NM_144997](https://www.ncbi.nlm.nih.gov/nuccore/NM_144997) |
| dbSNP | [rs2544194629](https://www.ncbi.nlm.nih.gov/snp/rs2544194629/) |
| Variant type | Duplication |
| Location | chr17:17219090-17219091 (GRCh38) |
| ClinVar | [VCV2578507](https://www.ncbi.nlm.nih.gov/clinvar/variation/2578507/) |

**All HGVS expressions:** `LRG_325:g.23097_23098dup`, `LRG_325t1:c.989_990dup`, `NC_000017.10:g.17122405_17122406dup`, `NC_000017.11:g.17219091_17219092dup`, `NG_008001.2:g.23097_23098dup`, `NM_001353229.2:c.1043_1044dup`, `NM_001353230.2:c.989_990dup`, `NM_001353231.2:c.989_990dup`, `NM_144997.7:c.989_990dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.53, GERP -1.38, phastCons 0.181 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.487, pLI 0.9891), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**FLCN** population constraint: LOEUF 0.487, pLI 0.9891, missense-Z 1.9669; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **obsolete Birt-Hogg-Dube syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **331** lies in a UniProt-annotated variant site (in psp); a UniProt-annotated variant site (in bhd1); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 79.14, 60% of residues very-high.

**4 experimental structure(s)** (PDB): [3V42](https://www.rcsb.org/structure/3V42), [6NZD](https://www.rcsb.org/structure/6NZD), [6ULG](https://www.rcsb.org/structure/6ULG), [8DHB](https://www.rcsb.org/structure/8DHB).

## What this gene does {#gene-function}

*Describes the biological roles of FLCN (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FLCN's established molecular role includes enzyme inhibitor activity. p.Ser331fs falls in the disordered region.


### Pathways affected {#pathways}

FLCN participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amino acids regulate mTORC1](https://reactome.org/content/detail/R-HSA-9639288) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** enzyme inhibitor activity, GTPase activator activity, enzyme binding, protein-containing complex binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, cellular response to starvation, positive regulation of autophagy, positive regulation of TOR signaling, lysosome localization, cellular response to amino acid starvation.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-07-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine | Pathogenic | no assertion criteria provided | clinical testing | 2023-07-01 |

## Associated conditions {#conditions}

[Birt-Hogg-Dube syndrome](https://sugi.bio/atlas/disease/birt-hogg-dube-syndrome/).

**Reported phenotype names (ClinVar):** Birt-Hogg-Dube syndrome, Birt Hogg Dubé syndrome.

## Similar variants {#similar}

Related FLCN variant pages (same residue, condition, or type): [FLCN p.Ser331del](/variant/flcn-p-ser331del), [FLCN p.Ser331Pro](/variant/flcn-p-ser331pro), [FLCN p.Ser331=](/variant/flcn-p-ser331), [FLCN p.Ser331Cys](/variant/flcn-p-ser331cys), [FLCN p.Ser331Phe](/variant/flcn-p-ser331phe), [FLCN p.Ser331Tyr](/variant/flcn-p-ser331tyr), [FLCN p.Ala310fs](/variant/flcn-p-ala310fs), [FLCN p.Ala412fs](/variant/flcn-p-ala412fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2578507). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*