# NM_001457.4(FLNB):c.7209G>A (p.Ser2403=)

https://sugi.bio/variant/flnb-p-ser2403

## Summary

**FLNB p.Ser2403= (c.7209G>A)** is classified **Benign** in FLNB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 11.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with FLNB-Related Spectrum Disorders.

**At a glance:** Benign · review: Multiple submitters · rsID rs13079906 · 6 submitters · 1 linked condition · common (popmax 11.2%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the FLNB gene that is classified as benign — not considered disease-causing, submitted by 6 submitters, and is linked to FLNB-Related Spectrum Disorders.

*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.Ser2403= |
| Coding change (HGVS c.) | c.7209G>A |
| MANE Select transcript | [NM_001457](https://www.ncbi.nlm.nih.gov/nuccore/NM_001457) |
| dbSNP | [rs13079906](https://www.ncbi.nlm.nih.gov/snp/rs13079906/) |
| Variant type | single nucleotide variant |
| Location | chr3:58168450-58168450 (GRCh38) |
| ClinVar | [VCV258121](https://www.ncbi.nlm.nih.gov/clinvar/variation/258121/) |

**All HGVS expressions:** `NC_000003.11:g.58154177G>A`, `NC_000003.12:g.58168450G>A`, `NG_012801.1:g.165051G>A`, `NM_001164317.2:c.7302G>A`, `NM_001164318.2:c.7176G>A`, `NM_001164319.2:c.7137G>A`, `NM_001457.4:c.7209G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 11.2%, nfe) — too common for a highly-penetrant pathogenic allele.

- **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 -3.505, GERP -5.66 — fast-evolving / accelerated position
- CADD: **PHRED 10.12**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.20 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **11.2%** (nfe) · FAF95 11.2% · FAF99 11.2% · 132,238/1,178,064 in the highest group · 165,037/1,612,022 alleles overall — common (popmax 11.2%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 16.2% | 6 |
| Finnish (not grpmax-eligible) | 14.5% | 7 |
| European (non-Finnish) (grpmax) | 11.2% | 9 |
| Remaining individuals (not grpmax-eligible) | 9.01% | 11 |
| Admixed American | 8.52% | 12 |
| South Asian | 6.64% | 15 |
| Ashkenazi Jewish (not grpmax-eligible) | 6.44% | 16 |
| African / African-American | 5.9% | 17 |
| Middle Eastern | 3.6% | 28 |
| East Asian | 0.0535% | 1,870 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **2403** lies in a β-strand; the 'interaction with inppl1' region.

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. p.Ser2403= falls in the interaction with inppl1 region.


### 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (6/6 Benign).

**Submission history:** 6 submissions (2016–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-03-03 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[FLNB-Related Spectrum Disorders](https://sugi.bio/atlas/disease/flnb-related-spectrum-disorders/).

**Reported phenotype names (ClinVar):** FLNB-Related Spectrum Disorders, not specified, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related FLNB variant pages (same residue, condition, or type): [FLNB p.Ser2403Leu](/variant/flnb-p-ser2403leu), [FLNB p.Glu1661Lys](/variant/flnb-p-glu1661lys), [FLNB p.Glu78Gly](/variant/flnb-p-glu78gly), [FLNB p.His1117Arg](/variant/flnb-p-his1117arg), [FLNB p.Leu1440Pro](/variant/flnb-p-leu1440pro), [FLNB p.Pro396Ser](/variant/flnb-p-pro396ser), [FLNB p.Ser1096Phe](/variant/flnb-p-ser1096phe), [FLNB p.Ser188Cys](/variant/flnb-p-ser188cys).

### 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 258121). 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.*