# NM_001101.5(ACTB):c.559_562del (p.Asp187fs)

https://sugi.bio/variant/actb-p-asp187fs

## Summary

**ACTB p.Asp187fs (c.559_562del)** is classified **Conflicting classifications of pathogenicity** in ACTB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-06). No gnomAD frequency available for this variant; Associated with Baraitser-Winter syndrome 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs886041265 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ACTB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Baraitser-Winter syndrome 1.

*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/0015189/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTB](https://sugi.bio/atlas/gene/ACTB/) |
| Protein change (HGVS p.) | p.Asp187fs |
| Coding change (HGVS c.) | c.559_562del |
| MANE Select transcript | [NM_001101](https://www.ncbi.nlm.nih.gov/nuccore/NM_001101) |
| dbSNP | [rs886041265](https://www.ncbi.nlm.nih.gov/snp/rs886041265/) |
| Variant type | Microsatellite |
| Location | chr7:5528521-5528524 (GRCh38) |
| ClinVar | [VCV279937](https://www.ncbi.nlm.nih.gov/clinvar/variation/279937/) |

**All HGVS expressions:** `LRG_132:g.7074GACT[1]`, `LRG_132t1:c.559_562del`, `NC_000007.13:g.5568154TCAG[1]`, `NC_000007.14:g.5528523TCAG[1]`, `NG_007992.1:g.7074GACT[1]`, `NM_001101.3:c.559_562delGACT`, `NM_001101.5:c.559_562del`

## 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 5.025, GERP 0.869, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.193, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 6**, so the transcript is predicted to undergo NMD.
- 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.
- Repeat context: **segmental_duplication** (chr18:62441999, chr5:80299094, chr9:100731360). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ACTB** population constraint: LOEUF 0.193, pLI 1, missense-Z 7.6921; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **ACTB-associated syndromic thrombocytopenia** — Moderate (AD)
- **Baraitser-Winter cerebrofrontofacial syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **187** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.31, 93% of residues very-high.

**93 experimental structure(s)** (PDB): [21VV](https://www.rcsb.org/structure/21VV), [3BYH](https://www.rcsb.org/structure/3BYH), [3D2U](https://www.rcsb.org/structure/3D2U), [3J82](https://www.rcsb.org/structure/3J82), [3LUE](https://www.rcsb.org/structure/3LUE), [6ANU](https://www.rcsb.org/structure/6ANU) — incl. mutant structure 6OX4.

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

*Describes the biological roles of ACTB (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.*

**How this variant is thought to act:** ACTB's established molecular role includes ATP hydrolysis activity. In Reactome, ACTB is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by BRAF and RAF1 fusions**.

**Disease mechanism (Reactome):** ACTB loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952), [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223).

### Pathways affected {#pathways}

ACTB participates in **46 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | electronic |
| [B-WICH complex positively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-5250924) | curated |
| [Cell-extracellular matrix interactions](https://reactome.org/content/detail/R-HSA-446353) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [DNA Damage Recognition in GG-NER](https://reactome.org/content/detail/R-HSA-5696394) | curated |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | curated |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | curated |
| [Formation of annular gap junctions](https://reactome.org/content/detail/R-HSA-196025) | curated |
| [Formation of the canonical BAF (cBAF) complex](https://reactome.org/content/detail/R-HSA-9933937) | curated |
| [Formation of the embryonic stem cell BAF (esBAF) complex](https://reactome.org/content/detail/R-HSA-9933946) | curated |
| [Formation of the non-canonical BAF (ncBAF) complex](https://reactome.org/content/detail/R-HSA-9933947) | curated |
| [Formation of the polybromo-BAF (pBAF) complex](https://reactome.org/content/detail/R-HSA-9933939) | curated |
| [GBP-mediated host defense](https://reactome.org/content/detail/R-HSA-9953170) | curated |
| [Gap junction degradation](https://reactome.org/content/detail/R-HSA-190873) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [RHO GTPases activate IQGAPs](https://reactome.org/content/detail/R-HSA-5626467) | curated |
| [RHOF GTPase cycle](https://reactome.org/content/detail/R-HSA-9035034) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [SWI/SNF chromatin remodelers](https://reactome.org/content/detail/R-HSA-9932451) | curated |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | electronic |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | electronic |
| [Folding of actin by CCT/TriC](https://reactome.org/content/detail/R-HSA-390450) | electronic |
| [Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)](https://reactome.org/content/detail/R-HSA-9934037) | electronic |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | electronic |
| [Prefoldin mediated transfer of substrate  to CCT/TriC](https://reactome.org/content/detail/R-HSA-389957) | electronic |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | electronic |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | electronic |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | electronic |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | electronic |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | electronic |
| [Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)](https://reactome.org/content/detail/R-HSA-9845323) | electronic |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |
| [Translocation of SLC2A4 (GLUT4) to the plasma membrane](https://reactome.org/content/detail/R-HSA-1445148) | electronic |

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

**Molecular function:** ATP hydrolysis activity, kinesin binding, protein kinase binding, nitric-oxide synthase regulator activity, Tat protein binding, identical protein binding.

**Biological process:** morphogenesis of a polarized epithelium, chromatin remodeling, establishment or maintenance of cell polarity, substantia nigra development, adherens junction assembly, apical protein localization.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-06.

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

**Submission history:** 2 submissions (2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-02-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-12 |

## Associated conditions {#conditions}

[Baraitser-Winter syndrome 1](https://sugi.bio/atlas/disease/baraitser-winter-syndrome-1/).

**Reported phenotype names (ClinVar):** Baraitser-Winter syndrome 1, not provided, MENTAL RETARDATION WITH EPILEPSY AND CHARACTERISTIC FACIES, PACHYGYRIA, MENTAL RETARDATION, EPILEPSY, AND CHARACTERISTIC FACIES, Cerebrofrontofacial syndrome, BARAITSER-WINTER SYNDROME 1, ATYPICAL, none provided.

## Similar variants {#similar}

Related ACTB variant pages (same residue, condition, or type): [ACTB p.Asp187=](/variant/actb-p-asp187), [ACTB p.Asp4del](/variant/actb-p-asp4del), [ACTB p.Asp187Glu](/variant/actb-p-asp187glu), [ACTB c.124-11TTCC[3]](/variant/actb-c-124-minus-11ttcc-3), [ACTB c.124-19_124-17del](/variant/actb-c-124-minus-19-124-minus-17del), [ACTB c.985-5_985-3del](/variant/actb-c-985-minus-5-985-minus-3del), [ACTB p.Ala22Thr](/variant/actb-p-ala22thr), [ACTB p.Ala7Thr](/variant/actb-p-ala7thr).

### 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 279937). 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.*