# NM_138638.5(CFL2):c.248C>T (p.Ala83Val)

https://sugi.bio/variant/cfl2-p-ala83val

## Summary

**CFL2 p.Ala83Val (c.248C>T)** is classified **Uncertain significance** in CFL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-28). AlphaMissense: likely pathogenic (0.9207); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1555333790 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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 1 submitter.

*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.Ala83Val |
| Coding change (HGVS c.) | c.248C>T |
| MANE Select transcript | [NM_138638](https://www.ncbi.nlm.nih.gov/nuccore/NM_138638) |
| dbSNP | [rs1555333790](https://www.ncbi.nlm.nih.gov/snp/rs1555333790/) |
| Variant type | single nucleotide variant |
| Location | chr14:34713317-34713317 (GRCh38) |
| ClinVar | [VCV546737](https://www.ncbi.nlm.nih.gov/clinvar/variation/546737/) |

**All HGVS expressions:** `LRG_213:g.6507C>T`, `NC_000014.8:g.35182523G>A`, `NC_000014.9:g.34713317G>A`, `NG_012740.1:g.6507C>T`, `NM_001243645.2:c.197C>T`, `NM_021914.8:c.248C>T`, `NM_138638.5:c.248C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9207)
- REVEL 0.235 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.872 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 11.914, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.9**. 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, Δ0.29 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **83** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-02-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-02-28 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## 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.Ser94Phe](/variant/cfl2-p-ser94phe), [CFL2 p.Thr25Ala](/variant/cfl2-p-thr25ala).

### 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 546737). 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.*