# NM_138638.5(CFL2):c.267C>T (p.Tyr89=)

https://sugi.bio/variant/cfl2-p-tyr89

## Summary

**CFL2 p.Tyr89= (c.267C>T)** is classified **Likely benign** in CFL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0329%, mid); Associated with nemaline myopathy 7.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs142164698 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the CFL2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 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.Tyr89= |
| Coding change (HGVS c.) | c.267C>T |
| MANE Select transcript | [NM_138638](https://www.ncbi.nlm.nih.gov/nuccore/NM_138638) |
| dbSNP | [rs142164698](https://www.ncbi.nlm.nih.gov/snp/rs142164698/) |
| Variant type | single nucleotide variant |
| Location | chr14:34713298-34713298 (GRCh38) |
| ClinVar | [VCV1091002](https://www.ncbi.nlm.nih.gov/clinvar/variation/1091002/) |

**All HGVS expressions:** `LRG_213:g.6526C>T`, `NC_000014.8:g.35182504G>A`, `NC_000014.9:g.34713298G>A`, `NG_012740.1:g.6526C>T`, `NM_001243645.2:c.216C>T`, `NM_021914.7:c.267C>T`, `NM_021914.8:c.267C>T`, `NM_138638.5:c.267C>T`

## Computational & population evidence {#evidence}

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

- **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 7.682, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.95**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0329%** (mid) · FAF95 0.00663% · FAF99 0.00579% · 2/6,080 in the highest group · 117/1,612,770 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,040 |
| Remaining individuals (not grpmax-eligible) | 0.0256% | 3,904 |
| Admixed American | 0.0134% | 7,478 |
| European (non-Finnish) | 0.00754% | 13,255 |
| African / African-American | 0.00134% | 74,648 |
| South Asian | 0.0011% | 90,840 |

*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 **89** lies in the adf-h domain; a β-strand; 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-30.

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

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | likely benign | criteria provided, single submitter | clinical testing | 2024-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-30 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Nemaline myopathy 7, not specified, AllHighlyPenetrant, 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 p.Val57Met](/variant/cfl2-p-val57met).

### 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 1091002). 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.*