# NM_001457.4(FLNB):c.1398_1420del (p.Val467fs)

https://sugi.bio/variant/flnb-p-val467fs

## Summary

**FLNB p.Val467fs (c.1398_1420del)** is classified **Pathogenic** in FLNB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-15). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2471064241 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FLNB gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FLNB](https://sugi.bio/atlas/gene/FLNB/) |
| Protein change (HGVS p.) | p.Val467fs |
| Coding change (HGVS c.) | c.1398_1420del |
| MANE Select transcript | [NM_001457](https://www.ncbi.nlm.nih.gov/nuccore/NM_001457) |
| dbSNP | [rs2471064241](https://www.ncbi.nlm.nih.gov/snp/rs2471064241/) |
| Variant type | Deletion |
| Location | chr3:58102254-58102276 (GRCh38) |
| ClinVar | [VCV2850493](https://www.ncbi.nlm.nih.gov/clinvar/variation/2850493/) |

**All HGVS expressions:** `NC_000003.11:g.58087982_58088004del`, `NC_000003.12:g.58102255_58102277del`, `NG_012801.1:g.98856_98878del`, `NM_001164317.2:c.1398_1420del`, `NM_001164318.2:c.1398_1420del`, `NM_001164319.2:c.1398_1420del`, `NM_001457.4:c.1398_1420del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.872, GERP 2.72, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.504, pLI 0.00057489. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 46**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**FLNB** population constraint: LOEUF 0.504, pLI 0.00057489, missense-Z 4.5491; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **FLNB-associated autosomal dominant filamin related bone disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.96, 7% of residues very-high.

**23 experimental structure(s)** (PDB): [2DI8](https://www.rcsb.org/structure/2DI8), [2DI9](https://www.rcsb.org/structure/2DI9), [2DIA](https://www.rcsb.org/structure/2DIA), [2DIB](https://www.rcsb.org/structure/2DIB), [2DIC](https://www.rcsb.org/structure/2DIC), [2DJ4](https://www.rcsb.org/structure/2DJ4) — incl. mutant structure 2WA6.

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

*Describes the biological roles of FLNB (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:** FLNB's established molecular role includes RNA binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |

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

**Molecular function:** RNA binding, identical protein binding, cadherin binding.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-15 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related FLNB variant pages (same residue, condition, or type): [FLNB p.Val467Ile](/variant/flnb-p-val467ile), [FLNB p.Glu1000fs](/variant/flnb-p-glu1000fs), [FLNB p.Glu1792del](/variant/flnb-p-glu1792del), [FLNB c.2056-15_2056-10del](/variant/flnb-c-2056-minus-15-2056-minus-10del), [FLNB c.2055+274del](/variant/flnb-c-2055-plus-274del), [FLNB c.3724+13_3724+15del](/variant/flnb-c-3724-plus-13-3724-plus-15del), [FLNB c.3724+35_3724+36del](/variant/flnb-c-3724-plus-35-3724-plus-36del), [FLNB c.3724+36del](/variant/flnb-c-3724-plus-36del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2850493). 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.*