# NM_016188.5(ACTL6B):c.435CTT[2] (p.Phe147del)

https://sugi.bio/variant/actl6b-p-phe147del

## Summary

**ACTL6B p.Phe147del (c.435CTT[2])** is classified **Conflicting classifications of pathogenicity** in ACTL6B (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-08-28). Very rare (popmax 0.00167%, amr); Associated with developmental and epileptic encephalopathy, 76.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs772520618 · 5 submitters · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ACTL6B gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to developmental and epileptic encephalopathy, 76.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016355/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTL6B](https://sugi.bio/atlas/gene/ACTL6B/) |
| Protein change (HGVS p.) | p.Phe147del |
| Coding change (HGVS c.) | c.435CTT[2] |
| MANE Select transcript | [NM_016188](https://www.ncbi.nlm.nih.gov/nuccore/NM_016188) |
| dbSNP | [rs772520618](https://www.ncbi.nlm.nih.gov/snp/rs772520618/) |
| Variant type | Microsatellite |
| Location | chr7:100650062-100650064 (GRCh38) |
| ClinVar | [VCV635103](https://www.ncbi.nlm.nih.gov/clinvar/variation/635103/) |

**All HGVS expressions:** `NC_000007.13:g.100247685AAG[2]`, `NC_000007.14:g.100650062AAG[2]`, `NM_016188.4:c.441_443delCTT`, `NM_016188.4:c.441delCTT`, `NM_016188.5:c.435CTT[2]`, `NM_016188.5:c.441_443delCTT`, `NR_134539.2:n.529CTT[2]`

## 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 -1.133, GERP 1.42, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 20.9**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000803% · FAF99 0.00065% · 1/59,978 in the highest group · 18/1,613,796 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,978 |
| European (non-Finnish) | 0.00136% | 73,748 |
| African / African-American | 0.00134% | 74,898 |

*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}

**ACTL6B** population constraint: LOEUF 0.954, pLI 9.6229e-13, missense-Z 3.3742; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **147** lies in a UniProt-annotated variant site (in dee76); a UniProt-annotated variant site (in dee76; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 91.52, 88% of residues very-high.

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

*Describes the biological roles of ACTL6B (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}

ACTL6B participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RMTs methylate histone arginines](https://reactome.org/content/detail/R-HSA-3214858) | curated |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | curated |
| [Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)](https://reactome.org/content/detail/R-HSA-9934037) | electronic |

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

**Biological process:** chromatin remodeling, dendrite development, neuron maturation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-08-28.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| SIB Swiss Institute of Bioinformatics | Uncertain significance | criteria provided, single submitter | curation | 2019-07-28 |
| CHU Sainte-Justine Research Center, University of Montreal | Likely pathogenic | no assertion criteria provided | research | 2019-03-01 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2020-11-25 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-08-28 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 76](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-76/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 76, ACTL6B-related recessive epilepsy, not provided, EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 76, DEVELOPMENTAL DELAY, EPILEPTIC ENCEPHALOPATHY, CEREBRAL ATROPHY, AND ABNORMAL MYELINATION, none provided.

## Similar variants {#similar}

Related ACTL6B variant pages (same residue, condition, or type): [ACTL6B p.Lys237del](/variant/actl6b-p-lys237del), [ACTL6B p.Arg97Ter](/variant/actl6b-p-arg97ter), [ACTL6B p.Gln186Ter](/variant/actl6b-p-gln186ter), [ACTL6B p.Gln278Ter](/variant/actl6b-p-gln278ter), [ACTL6B p.Gly349Ser](/variant/actl6b-p-gly349ser), [ACTL6B p.Gly50fs](/variant/actl6b-p-gly50fs), [ACTL6B p.Trp247Ter](/variant/actl6b-p-trp247ter), [ACTL6B p.Glu297Lys](/variant/actl6b-p-glu297lys).

### 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 635103). 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.*