# NM_001458.5(FLNC):c.1518C>T (p.Ser506=)

https://sugi.bio/variant/flnc-p-ser506

## Summary

**FLNC p.Ser506= (c.1518C>T)** is classified **Benign/Likely benign** in FLNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Rare (popmax 0.445%, sas); Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs368101036 · 5 submitters · 4 linked conditions · rare (popmax 0.445%, sas)

## For patients & families {#patients}

This is a change in the FLNC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Cardiovascular phenotype.

*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 | [FLNC](https://sugi.bio/atlas/gene/FLNC/) |
| Protein change (HGVS p.) | p.Ser506= |
| Coding change (HGVS c.) | c.1518C>T |
| MANE Select transcript | [NM_001458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001458) |
| dbSNP | [rs368101036](https://www.ncbi.nlm.nih.gov/snp/rs368101036/) |
| Variant type | single nucleotide variant |
| Location | chr7:128840129-128840129 (GRCh38) |
| ClinVar | [VCV471979](https://www.ncbi.nlm.nih.gov/clinvar/variation/471979/) |

**All HGVS expressions:** `LRG_870:g.14701C>T`, `LRG_870t1:c.1518C>T`, `NC_000007.13:g.128480183C>T`, `NC_000007.14:g.128840129C>T`, `NG_011807.1:g.14701C>T`, `NM_001127487.2:c.1518C>T`, `NM_001458.5:c.1518C>T`

## 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 -9.889 — fast-evolving / accelerated position
- CADD: **PHRED 4.708**. 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 (C>G, Δ0.31 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 **0.445%** (sas) · FAF95 0.409% · FAF99 0.395% · 405/91,088 in the highest group · 502/1,614,004 alleles overall — rare (popmax 0.445%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.445% | 225 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,126 |
| Middle Eastern | 0.0165% | 6,062 |
| Admixed American | 0.01% | 10,004 |
| European (non-Finnish) | 0.00576% | 17,353 |
| East Asian | 0.00223% | 44,884 |
| African / African-American | 0.00133% | 75,032 |

*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}

**FLNC** population constraint: LOEUF 0.424, pLI 1, missense-Z 5.9661; 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):

- **myofibrillar myopathy** — Definitive (AD)
- **dilated cardiomyopathy** — Definitive (AD)

## Protein context {#protein}


**14 experimental structure(s)** (PDB): [1V05](https://www.rcsb.org/structure/1V05), [2D7M](https://www.rcsb.org/structure/2D7M), [2D7N](https://www.rcsb.org/structure/2D7N), [2D7O](https://www.rcsb.org/structure/2D7O), [2D7P](https://www.rcsb.org/structure/2D7P), [2D7Q](https://www.rcsb.org/structure/2D7Q).

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

*Describes the biological roles of FLNC (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:** FLNC's established molecular role includes cytoskeletal protein binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell-extracellular matrix interactions](https://reactome.org/content/detail/R-HSA-446353) | curated |

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

**Molecular function:** cytoskeletal protein binding, ankyrin binding, identical protein binding.

**Biological process:** sarcomere organization.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (3 Likely benign, 2 Benign).

**Submission history:** 5 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-09-06 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2024-12-30 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-25 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [myofibrillar myopathy 5](https://sugi.bio/atlas/disease/myofibrillar-myopathy-5/), [distal myopathy with posterior leg and anterior hand involvement](https://sugi.bio/atlas/disease/distal-myopathy-with-posterior-leg-and-anterior-hand-involvement/), [hypertrophic cardiomyopathy 26](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-26/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, not specified, Distal myopathy with posterior leg and anterior hand involvement, Hypertrophic cardiomyopathy 26, Myofibrillar myopathy 5, AllHighlyPenetrant, none provided, FILAMINOPATHY, AUTOSOMAL DOMINANT, Filaminopathy (type).

## Similar variants {#similar}

Related FLNC variant pages (same residue, condition, or type): [FLNC p.Ser506Asn](/variant/flnc-p-ser506asn), [FLNC c.1047+1G>T](/variant/flnc-c-1047-plus-1g-t), [FLNC c.1048-1G>A](/variant/flnc-c-1048-minus-1g-a), [FLNC c.1210+1G>A](/variant/flnc-c-1210-plus-1g-a), [FLNC c.1549+2T>G](/variant/flnc-c-1549-plus-2t-g), [FLNC c.2007+1G>A](/variant/flnc-c-2007-plus-1g-a), [FLNC c.2550+1G>C](/variant/flnc-c-2550-plus-1g-c), [FLNC c.2550+2T>C](/variant/flnc-c-2550-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 471979). 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.*