# NM_001458.5(FLNC):c.1032C>T (p.Val344=)

https://sugi.bio/variant/flnc-p-val344

## Summary

**FLNC p.Val344= (c.1032C>T)** is classified **Benign** in FLNC (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 29.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with distal myopathy with posterior leg and anterior hand involvement.

**At a glance:** Benign · review: Multiple submitters · rsID rs2291562 · 13 submitters · 3 linked conditions · common (popmax 29.1%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the FLNC gene that is classified as benign — not considered disease-causing, submitted by 13 submitters, and is linked to distal myopathy with posterior leg and anterior hand involvement.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult |
| Diagnostic panels | FLNC is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of FLNC-related handgrip and calf weakness-distal myopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intrinsic hand muscle atrophy — Very frequent (99-80%)
- Exercise-induced myalgia — Very frequent (99-80%)
- Hyporeflexia of lower limbs — Very frequent (99-80%)
- Inability to walk — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Finger flexor weakness — Frequent (79-30%)
- Distal lower limb muscle weakness — Frequent (79-30%)
- Foot dorsiflexor weakness — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016666/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.Val344= |
| Coding change (HGVS c.) | c.1032C>T |
| MANE Select transcript | [NM_001458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001458) |
| dbSNP | [rs2291562](https://www.ncbi.nlm.nih.gov/snp/rs2291562/) |
| Variant type | single nucleotide variant |
| Location | chr7:128838049-128838049 (GRCh38) |
| ClinVar | [VCV129078](https://www.ncbi.nlm.nih.gov/clinvar/variation/129078/) |

**All HGVS expressions:** `LRG_870:g.12621C>T`, `LRG_870t1:c.1032C>T`, `NC_000007.13:g.128478103C>T`, `NC_000007.14:g.128838049C>T`, `NG_011807.1:g.12621C>T`, `NM_001127487.2:c.1032C>T`, `NM_001458.5:c.1032C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 29.1%, eas) — 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 -8.731 — fast-evolving / accelerated position
- CADD: **PHRED 1.367**. 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>A, Δ0.67 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 **29.1%** (eas) · FAF95 28.7% · FAF99 28.5% · 13,050/44,858 in the highest group · 99,666/1,613,168 alleles overall — common (popmax 29.1%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 29.1% | 3 |
| African / African-American | 28.1% | 4 |
| Admixed American | 13.6% | 7 |
| South Asian | 8.46% | 12 |
| Remaining individuals (not grpmax-eligible) | 6.82% | 15 |
| Middle Eastern | 4.26% | 23 |
| European (non-Finnish) | 3.65% | 27 |
| Finnish (not grpmax-eligible) | 2.65% | 38 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.79% | 56 |
| Amish (not grpmax-eligible) | 0.329% | 304 |

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

**Submitter consensus:** unanimous (13/13 Benign).

**Submission history:** 13 submissions (2013–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-12-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2013-08-15 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2015-01-13 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2023-04-10 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2018-12-26 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-04-26 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-02-12 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

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

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

## 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 2026-10-15); 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 129078). 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.*