# NM_138638.5(CFL2):c.154_157del (p.Ala52fs)

https://sugi.bio/variant/cfl2-p-ala52fs

## Summary

**CFL2 p.Ala52fs (c.154_157del)** is classified **Pathogenic** in CFL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-31). No gnomAD frequency available for this variant; Associated with nemaline myopathy 7.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2502579467 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CFL2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to nemaline myopathy 7.

*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, Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | CFL2 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Typical nemaline myopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- High palate — Frequent (79-30%)
- Hyporeflexia — Frequent (79-30%)
- Gait disturbance — Frequent (79-30%)
- Neonatal hypotonia — Frequent (79-30%)
- Respiratory insufficiency — Frequent (79-30%)
- Limb-girdle muscle weakness — Frequent (79-30%)
- Axial muscle weakness — Frequent (79-30%)
- Increased variability in muscle fiber diameter — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015493/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CFL2](https://sugi.bio/atlas/gene/CFL2/) |
| Protein change (HGVS p.) | p.Ala52fs |
| Coding change (HGVS c.) | c.154_157del |
| MANE Select transcript | [NM_138638](https://www.ncbi.nlm.nih.gov/nuccore/NM_138638) |
| dbSNP | [rs2502579467](https://www.ncbi.nlm.nih.gov/snp/rs2502579467/) |
| Variant type | Deletion |
| Location | chr14:34713408-34713411 (GRCh38) |
| ClinVar | [VCV2000758](https://www.ncbi.nlm.nih.gov/clinvar/variation/2000758/) |

**All HGVS expressions:** `LRG_213:g.6413_6416del`, `LRG_213t1:c.152_155del`, `NC_000014.8:g.35182616_35182619del`, `NC_000014.9:g.34713410_34713413del`, `NG_012740.1:g.6413_6416del`, `NM_001243645.2:c.103_106del`, `NM_021914.8:c.154_157del`, `NM_138638.5:c.154_157del`, `NR_028130.2:n.207_210del`, `NR_028132.1:n.270_273delAAGC`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.878, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.91, pLI 0.10827. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 4**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CFL2** population constraint: LOEUF 0.91, pLI 0.10827, missense-Z 1.3419. *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):

- **nemaline myopathy 7** — Definitive (AR)

## Protein context {#protein}

Residue **52** lies in the adf-h domain; the 'interaction with csrp3' region.

AlphaFold model confidence (whole protein): pLDDT 88.78, 51% of residues very-high.

**11 experimental structure(s)** (PDB): [7M0G](https://www.rcsb.org/structure/7M0G), [7U8K](https://www.rcsb.org/structure/7U8K), [9Q7K](https://www.rcsb.org/structure/9Q7K), [9Q7L](https://www.rcsb.org/structure/9Q7L), [9Q7M](https://www.rcsb.org/structure/9Q7M), [9Q7N](https://www.rcsb.org/structure/9Q7N).

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-31.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-31 |

## Associated conditions {#conditions}

[nemaline myopathy 7](https://sugi.bio/atlas/disease/nemaline-myopathy-7/).

**Reported phenotype names (ClinVar):** Nemaline myopathy 7, Nemaline myopathy 7, autosomal recessive.

## Similar variants {#similar}

Related CFL2 variant pages (same residue, condition, or type): [CFL2 c.312-7del](/variant/cfl2-c-312-minus-7del), [CFL2 p.Ser113fs](/variant/cfl2-p-ser113fs), [CFL2 p.Glu28del](/variant/cfl2-p-glu28del), [CFL2 p.Tyr117fs](/variant/cfl2-p-tyr117fs), [CFL2 c.312-8_312-7del](/variant/cfl2-c-312-minus-8-312-minus-7del), [CFL2 c.389-8del](/variant/cfl2-c-389-minus-8del), [CFL2 c.389-9del](/variant/cfl2-c-389-minus-9del), [CFL2 p.Lys34fs](/variant/cfl2-p-lys34fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2000758). 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.*