# NM_001458.5(FLNC):c.22T>C (p.Ser8Pro)

https://sugi.bio/variant/flnc-p-ser8pro

## Summary

**FLNC p.Ser8Pro (c.22T>C)** is classified **Benign/Likely benign** in FLNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0841); Rare (popmax 0.152%, eas); Associated with distal myopathy with posterior leg and anterior hand involvement.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs544875797 · 5 submitters · 3 linked conditions · AlphaMissense likely benign · rare (popmax 0.152%, eas)

## 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 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.Ser8Pro |
| Coding change (HGVS c.) | c.22T>C |
| MANE Select transcript | [NM_001458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001458) |
| dbSNP | [rs544875797](https://www.ncbi.nlm.nih.gov/snp/rs544875797/) |
| Variant type | single nucleotide variant |
| Location | chr7:128830659-128830659 (GRCh38) |
| ClinVar | [VCV774783](https://www.ncbi.nlm.nih.gov/clinvar/variation/774783/) |

**All HGVS expressions:** `LRG_870:g.5231T>C`, `LRG_870t1:c.22T>C`, `NC_000007.13:g.128470713T>C`, `NC_000007.14:g.128830659T>C`, `NG_011807.1:g.5231T>C`, `NM_001127487.2:c.22T>C`, `NM_001458.5:c.22T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0841)
- REVEL 0.135 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.369 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.481, phastCons 0.038 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.96**. 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 1.13** across the covering region of the MANE Select transcript (128,830,638–128,830,707), spanning 69 bp. Chi-square p 0.46. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.152%** (eas) · FAF95 0.123% · FAF99 0.112% · 68/44,826 in the highest group · 124/1,612,220 alleles overall — rare (popmax 0.152%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.152% | 659 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,120 |
| African / African-American | 0.004% | 25,004 |
| European (non-Finnish) | 0.0028% | 35,752 |

*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}

Residue **8** lies in the 'actin-binding' region; the 'disordered' region.

**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. p.Ser8Pro falls in the actin-binding region.


### 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 2026-01-28.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-03-25 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-02 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | criteria provided, single submitter | research | 2021-12-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## 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 provided, Cardiovascular phenotype, Hypertrophic cardiomyopathy 26, Myofibrillar myopathy 5, not specified, WILLIAMS DISTAL MYOPATHY, Cardiomyopathy, familial hypertrophic, 26, Filaminopathy (type), FILAMINOPATHY, AUTOSOMAL DOMINANT.

## 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 774783). 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.*