# NM_138638.5(CFL2):c.169G>A (p.Val57Met)

https://sugi.bio/variant/cfl2-p-val57met

## Summary

**CFL2 p.Val57Met (c.169G>A)** is classified **Uncertain significance** in CFL2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.6585); Ultra-rare (popmax 0.0135%, nfe); Associated with nemaline myopathy 7.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs200536303 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0135%, nfe)

## For patients & families {#patients}

This is a change in the CFL2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, 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.Val57Met |
| Coding change (HGVS c.) | c.169G>A |
| MANE Select transcript | [NM_138638](https://www.ncbi.nlm.nih.gov/nuccore/NM_138638) |
| dbSNP | [rs200536303](https://www.ncbi.nlm.nih.gov/snp/rs200536303/) |
| Variant type | single nucleotide variant |
| Location | chr14:34713396-34713396 (GRCh38) |
| ClinVar | [VCV954128](https://www.ncbi.nlm.nih.gov/clinvar/variation/954128/) |

**All HGVS expressions:** `LRG_213:g.6428G>A`, `NC_000014.8:g.35182602C>T`, `NC_000014.9:g.34713396C>T`, `NG_012740.1:g.6428G>A`, `NM_001243645.2:c.118G>A`, `NM_021914.8:c.169G>A`, `NM_138638.5:c.169G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6585)
- REVEL 0.518 (indeterminate)
- SaProt LLR -9.077 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.41) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.879, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.6**. 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 0.65** across the covering region of the MANE Select transcript (34,712,868–34,714,540), spanning 1,672 bp. Chi-square p 1.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.41**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0135%** (nfe) · FAF95 0.0117% · FAF99 0.0111% · 159/1,180,028 in the highest group · 234/1,613,992 alleles overall — ultra-rare (popmax 0.0135%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.106% | 942 |
| European (non-Finnish) (grpmax) | 0.0135% | 7,422 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,496 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,602 |
| South Asian | 0.0011% | 91,074 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **57** lies in an α-helix; 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-27.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 6 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-30 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-27 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-06 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Nemaline myopathy 7, Sarcoma, Gastric cancer, Thyroid cancer, nonmedullary, 1, not provided, none provided, Nemaline myopathy 7, autosomal recessive.

## Similar variants {#similar}

Related CFL2 variant pages (same residue, condition, or type): [CFL2 c.4-172C>T](/variant/cfl2-c-4-minus-172c-t), [CFL2 c.*1507C>T](/variant/cfl2-c-star-1507c-t), [CFL2 c.*1759A>G](/variant/cfl2-c-star-1759a-g), [CFL2 p.Leu153Val](/variant/cfl2-p-leu153val), [CFL2 p.Lys31Asn](/variant/cfl2-p-lys31asn), [CFL2 p.Met18Ile](/variant/cfl2-p-met18ile), [CFL2 p.Thr25Ala](/variant/cfl2-p-thr25ala), [CFL2 c.*1682A>T](/variant/cfl2-c-star-1682a-t).

### 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 954128). 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.*