# NM_001101.5(ACTB):c.669C>T (p.Phe223=)

https://sugi.bio/variant/actb-p-phe223

## Summary

**ACTB p.Phe223= (c.669C>T)** is classified **Likely benign** in ACTB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). Ultra-rare (popmax 0.0329%, mid); Associated with Baraitser-Winter syndrome 1.

**At a glance:** Likely benign · review: Single submitter · rsID rs369943480 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the ACTB gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Phe223= |
| Coding change (HGVS c.) | c.669C>T |
| MANE Select transcript | [NM_001101](https://www.ncbi.nlm.nih.gov/nuccore/NM_001101) |
| dbSNP | [rs369943480](https://www.ncbi.nlm.nih.gov/snp/rs369943480/) |
| Variant type | single nucleotide variant |
| Location | chr7:5528414-5528414 (GRCh38) |
| ClinVar | [VCV466231](https://www.ncbi.nlm.nih.gov/clinvar/variation/466231/) |

**All HGVS expressions:** `LRG_132:g.7188C>T`, `LRG_132t1:c.669C>T`, `NC_000007.13:g.5568045G>A`, `NC_000007.14:g.5528414G>A`, `NG_007992.1:g.7188C>T`, `NM_001101.5:c.669C>T`

## 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 1.831, GERP -0.39, phastCons 1 — weakly conserved position
- CADD: **PHRED 14.67**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0329%** (mid) · FAF95 0.00919% · FAF99 0.00735% · 2/6,082 in the highest group · 49/1,613,952 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,041 |
| South Asian | 0.0154% | 6,507 |
| Admixed American | 0.005% | 20,002 |
| African / African-American | 0.004% | 24,974 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| European (non-Finnish) | 0.00203% | 49,169 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,900 |

*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 **223** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-16.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-16 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Baraitser-Winter syndrome 1, BARAITSER-WINTER SYNDROME 1, ATYPICAL, PACHYGYRIA, MENTAL RETARDATION, EPILEPSY, AND CHARACTERISTIC FACIES, MENTAL RETARDATION WITH EPILEPSY AND CHARACTERISTIC FACIES, Cerebrofrontofacial syndrome.

## Similar variants {#similar}

Related ACTB variant pages (same residue, condition, or type): [ACTB p.Phe223Ser](/variant/actb-p-phe223ser), [ACTB p.Ala22Thr](/variant/actb-p-ala22thr), [ACTB p.Ala7Thr](/variant/actb-p-ala7thr), [ACTB p.Arg147Cys](/variant/actb-p-arg147cys), [ACTB p.Arg183Trp](/variant/actb-p-arg183trp), [ACTB p.Arg196Cys](/variant/actb-p-arg196cys), [ACTB p.Arg196His](/variant/actb-p-arg196his), [ACTB p.Arg196Leu](/variant/actb-p-arg196leu).

### 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 466231). 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.*