# NM_001458.5(FLNC):c.1499T>C (p.Phe500Ser)

https://sugi.bio/variant/flnc-p-phe500ser

## Summary

**FLNC p.Phe500Ser (c.1499T>C)** is classified **Uncertain significance** in FLNC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-03). AlphaMissense: ambiguous (0.3521); Very rare (popmax 8.47e-05%, nfe); Associated with hypertrophic cardiomyopathy 26.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2128934879 · 2 submitters · 3 linked conditions · AlphaMissense ambiguous · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the FLNC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to hypertrophic cardiomyopathy 26.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | FLNC is a diagnostic-grade gene on 10 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025029/index) · [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.Phe500Ser |
| Coding change (HGVS c.) | c.1499T>C |
| MANE Select transcript | [NM_001458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001458) |
| dbSNP | [rs2128934879](https://www.ncbi.nlm.nih.gov/snp/rs2128934879/) |
| Variant type | single nucleotide variant |
| Location | chr7:128840110-128840110 (GRCh38) |
| ClinVar | [VCV1503888](https://www.ncbi.nlm.nih.gov/clinvar/variation/1503888/) |

**All HGVS expressions:** `LRG_870:g.14682T>C`, `LRG_870t1:c.1499T>C`, `NC_000007.13:g.128480164T>C`, `NC_000007.14:g.128840110T>C`, `NG_011807.1:g.14682T>C`, `NM_001127487.2:c.1499T>C`, `NM_001458.4:c.1499T>C`, `NM_001458.5:c.1499T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.3521) — no call either way
- REVEL 0.288 (benign-leaning)
- SaProt LLR -6.808 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate
- Conservation: phyloP 4.178, phastCons 1 — highly conserved
- CADD: **PHRED 25.2**. 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.*
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (128,837,481–128,848,889), spanning 11,408 bp. Chi-square p 8.4e-13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.93 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 **8.47e-05%** (nfe) · 1/1,180,018 in the highest group · 1/1,614,110 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-05-03.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2020–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-11-21 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-03 |

## Associated conditions {#conditions}

[hypertrophic cardiomyopathy 26](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-26/), [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/).

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

## Same-residue context {#hotspot}

Residue **500** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FLNC p.Phe500fs](/variant/flnc-p-phe500fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FLNC variant pages (same residue, condition, or type): [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), [FLNC c.2930-1G>A](/variant/flnc-c-2930-minus-1g-a).

### 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 1503888). 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.*