# NM_001457.4(FLNB):c.1431T>G (p.Val477=)

https://sugi.bio/variant/flnb-p-val477

## Summary

**FLNB p.Val477= (c.1431T>G)** is classified **Likely benign** in FLNB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). Ultra-rare (popmax 0.0383%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0383%, amr)

## For patients & families {#patients}

This is a change in the FLNB gene that is classified as likely benign — not considered disease-causing, 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.Val477= |
| Coding change (HGVS c.) | c.1431T>G |
| MANE Select transcript | [NM_001457](https://www.ncbi.nlm.nih.gov/nuccore/NM_001457) |
| Variant type | single nucleotide variant |
| Location | chr3:58102288-58102288 (GRCh38) |
| ClinVar | [VCV3685037](https://www.ncbi.nlm.nih.gov/clinvar/variation/3685037/) |

**All HGVS expressions:** `NC_000003.11:g.58088015T>G`, `NC_000003.12:g.58102288T>G`, `NG_012801.1:g.98889T>G`, `NM_001164317.2:c.1431T>G`, `NM_001164318.2:c.1431T>G`, `NM_001164319.2:c.1431T>G`, `NM_001457.4:c.1431T>G`

## 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 0.11, GERP -4.9, phastCons 0.972 — weakly conserved position
- CADD: **PHRED 9.486**. 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 (T>A, Δ0.62 donor 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 **0.0383%** (amr) · FAF95 0.0261% · FAF99 0.0222% · 23/60,008 in the highest group · 23/1,614,080 alleles overall — ultra-rare (popmax 0.0383%, amr).

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-27.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

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

## Same-residue context {#hotspot}

Residue **477** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FLNB p.Val477fs](/variant/flnb-p-val477fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FLNB variant pages (same residue, condition, or type): [FLNB p.Val477fs](/variant/flnb-p-val477fs), [FLNB c.4390+2T>C](/variant/flnb-c-4390-plus-2t-c), [FLNB c.5110-1G>A](/variant/flnb-c-5110-minus-1g-a), [FLNB p.Arg1463Ter](/variant/flnb-p-arg1463ter), [FLNB p.Arg1948Ter](/variant/flnb-p-arg1948ter), [FLNB p.Arg649Ter](/variant/flnb-p-arg649ter), [FLNB p.Asp167Gly](/variant/flnb-p-asp167gly), [FLNB p.Glu227Lys](/variant/flnb-p-glu227lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3685037). 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.*