# NM_024855.4(ACTR5):c.1245G>C (p.Leu415Phe)

https://sugi.bio/variant/actr5-p-leu415phe

## Summary

**ACTR5 p.Leu415Phe (c.1245G>C)** is classified **Uncertain significance** in ACTR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1236); Ultra-rare (popmax 0.0253%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs199604949 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0253%, afr)

## For patients & families {#patients}

This is a change in the ACTR5 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 | [ACTR5](https://sugi.bio/atlas/gene/ACTR5/) |
| Protein change (HGVS p.) | p.Leu415Phe |
| Coding change (HGVS c.) | c.1245G>C |
| MANE Select transcript | [NM_024855](https://www.ncbi.nlm.nih.gov/nuccore/NM_024855) |
| dbSNP | [rs199604949](https://www.ncbi.nlm.nih.gov/snp/rs199604949/) |
| Variant type | single nucleotide variant |
| Location | chr20:38765470-38765470 (GRCh38) |
| ClinVar | [VCV2464844](https://www.ncbi.nlm.nih.gov/clinvar/variation/2464844/) |

**All HGVS expressions:** `NC_000020.10:g.37394113G>C`, `NC_000020.11:g.38765470G>C`, `NM_024855.4:c.1245G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1236)
- REVEL 0.455 (indeterminate)
- SaProt LLR -6.634 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 3.889, GERP 1.22, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.9**. 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 1.02** across the covering region of the MANE Select transcript (38,748,479–38,771,813), spanning 23,334 bp. Chi-square p 0.57. 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>T, Δ0.33 acceptor 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 **0.0253%** (afr) · FAF95 0.0165% · FAF99 0.0137% · 19/75,034 in the highest group · 48/1,614,132 alleles overall — ultra-rare (popmax 0.0253%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0253% | 3,949 |
| Middle Eastern | 0.0165% | 6,062 |
| European (non-Finnish) | 0.0022% | 45,385 |
| Admixed American | 0.00167% | 60,010 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,502 |

*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}

**ACTR5** population constraint: LOEUF 0.986, pLI 1.2267e-12, missense-Z -0.16572. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.75, 62% of residues very-high.

**6 experimental structure(s)** (PDB): [6HTS](https://www.rcsb.org/structure/6HTS), [7ZI4](https://www.rcsb.org/structure/7ZI4), [9GCG](https://www.rcsb.org/structure/9GCG), [9GE5](https://www.rcsb.org/structure/9GE5), [9GEV](https://www.rcsb.org/structure/9GEV), [9GFB](https://www.rcsb.org/structure/9GFB).

## What this gene does {#gene-function}

*Describes the biological roles of ACTR5 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

ACTR5 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage Recognition in GG-NER](https://reactome.org/content/detail/R-HSA-5696394) | curated |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** regulation of DNA replication, double-strand break repair, chromatin remodeling, regulation of chromosome organization, positive regulation of DNA-templated transcription, regulation of cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-15 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ACTR5 variant pages (same residue, condition, or type): [ACTR5 p.Ala11Thr](/variant/actr5-p-ala11thr), [ACTR5 p.Ala13Val](/variant/actr5-p-ala13val), [ACTR5 p.Ala14Thr](/variant/actr5-p-ala14thr), [ACTR5 p.Ala235Thr](/variant/actr5-p-ala235thr), [ACTR5 p.Ala253Thr](/variant/actr5-p-ala253thr), [ACTR5 p.Ala371Val](/variant/actr5-p-ala371val), [ACTR5 p.Ala541Gly](/variant/actr5-p-ala541gly), [ACTR5 p.Arg210His](/variant/actr5-p-arg210his).

### 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 2464844). 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.*