# NM_138638.5(CFL2):c.281C>T (p.Ser94Phe)

https://sugi.bio/variant/cfl2-p-ser94phe

## Summary

**CFL2 p.Ser94Phe (c.281C>T)** is classified **Uncertain significance** in CFL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9678); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0165%, mid)

## 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 2 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Ser94Phe |
| Coding change (HGVS c.) | c.281C>T |
| MANE Select transcript | [NM_138638](https://www.ncbi.nlm.nih.gov/nuccore/NM_138638) |
| Variant type | single nucleotide variant |
| Location | chr14:34713284-34713284 (GRCh38) |
| ClinVar | [VCV3380183](https://www.ncbi.nlm.nih.gov/clinvar/variation/3380183/) |

**All HGVS expressions:** `LRG_213:g.6540C>T`, `LRG_213t1:c.281C>T`, `NC_000014.8:g.35182490G>A`, `NC_000014.9:g.34713284G>A`, `NG_012740.1:g.6540C>T`, `NM_001243645.2:c.230C>T`, `NM_021914.8:c.281C>T`, `NM_138638.5:c.281C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9678)
- REVEL 0.371 (indeterminate)
- SaProt LLR -13.204 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 10.015, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.80 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 **0.0165%** (mid) · FAF95 0.000543% · FAF99 0.000429% · 1/6,072 in the highest group · 20/1,612,048 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,072 |
| Remaining individuals (not grpmax-eligible) | 0.00801% | 12,483 |
| Admixed American | 0.00168% | 59,698 |
| African / African-American | 0.00134% | 74,570 |
| European (non-Finnish) | 0.00102% | 98,290 |

*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 **94** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-26.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-11 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Similar variants {#similar}

Related CFL2 variant pages (same residue, condition, or type): [CFL2 p.Lys31Asn](/variant/cfl2-p-lys31asn), [CFL2 p.Thr25Ile](/variant/cfl2-p-thr25ile), [CFL2 p.Asp42Asn](/variant/cfl2-p-asp42asn), [CFL2 p.His133Arg](/variant/cfl2-p-his133arg), [CFL2 p.Ser147Leu](/variant/cfl2-p-ser147leu), [CFL2 p.Val159Ile](/variant/cfl2-p-val159ile), [CFL2 c.4-172C>T](/variant/cfl2-c-4-minus-172c-t), [CFL2 c.*1507C>T](/variant/cfl2-c-star-1507c-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 3380183). 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.*