# NM_001614.5(ACTG1):c.698C>T (p.Ser233Phe)

https://sugi.bio/variant/actg1-p-ser233phe

## Summary

**ACTG1 p.Ser233Phe (c.698C>T)** is classified **Uncertain significance** in ACTG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-09). AlphaMissense: likely pathogenic (0.8771); Very rare (popmax 0.0022%, sas); Associated with autosomal dominant nonsyndromic hearing loss 20.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1387098201 · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the ACTG1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to autosomal dominant nonsyndromic hearing loss 20.

*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/0018111/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTG1](https://sugi.bio/atlas/gene/ACTG1/) |
| Protein change (HGVS p.) | p.Ser233Phe |
| Coding change (HGVS c.) | c.698C>T |
| MANE Select transcript | [NM_001614](https://www.ncbi.nlm.nih.gov/nuccore/NM_001614) |
| dbSNP | [rs1387098201](https://www.ncbi.nlm.nih.gov/snp/rs1387098201/) |
| Variant type | single nucleotide variant |
| Location | chr17:81511292-81511292 (GRCh38) |
| ClinVar | [VCV2924802](https://www.ncbi.nlm.nih.gov/clinvar/variation/2924802/) |

**All HGVS expressions:** `NC_000017.10:g.79478318G>A`, `NC_000017.11:g.81511292G>A`, `NG_011433.1:g.6510C>T`, `NG_015964.2:g.1232G>A`, `NM_001199954.3:c.698C>T`, `NM_001614.5:c.698C>T`, `NR_037688.3:n.770C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8771)
- REVEL 0.756 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.673 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 2.424, GERP 1.87, phastCons 0.139 — highly conserved (agrees)
- CADD: **PHRED 21.7**. 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 0.74** across the covering region of the MANE Select transcript (81,511,091–81,511,356), spanning 265 bp. Chi-square p 0.016. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0022%** (sas) · FAF95 0.0005% · FAF99 0.000366% · 2/91,094 in the highest group · 17/1,613,738 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,606 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,242 |
| South Asian (grpmax) | 0.0022% | 45,547 |
| Admixed American | 0.00167% | 60,010 |
| European (non-Finnish) | 0.000932% | 107,277 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ACTG1** population constraint: LOEUF 0.617, pLI 0.45871, missense-Z 4.8895. *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):

- **Baraitser-winter syndrome 2** — Definitive (AD)
- **nonsyndromic genetic hearing loss** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 95.44, 93% of residues very-high.

**11 experimental structure(s)** (PDB): [5JLH](https://www.rcsb.org/structure/5JLH), [6CXI](https://www.rcsb.org/structure/6CXI), [6CXJ](https://www.rcsb.org/structure/6CXJ), [6G2T](https://www.rcsb.org/structure/6G2T), [6V62](https://www.rcsb.org/structure/6V62), [6V63](https://www.rcsb.org/structure/6V63) — incl. mutant structure 6V62.

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

*Describes the biological roles of ACTG1 (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:** ACTG1's established molecular role includes profilin binding. In Reactome, ACTG1 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):** ACTG1 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}

ACTG1 participates in **30 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 |
| [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 |
| [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 |
| [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 |
| [RHOBTB2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013418) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | 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 |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | 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 actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | 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 |
| [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:** profilin binding, ubiquitin protein ligase binding, identical protein binding.

**Biological process:** angiogenesis, morphogenesis of a polarized epithelium, positive regulation of gene expression, positive regulation of cell migration, regulation of stress fiber assembly, regulation of focal adhesion assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-09.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-09 |

## Associated conditions {#conditions}

[autosomal dominant nonsyndromic hearing loss 20](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-20/), [Baraitser-winter syndrome 2](https://sugi.bio/atlas/disease/baraitser-winter-syndrome-2/).

**Reported phenotype names (ClinVar):** Autosomal dominant nonsyndromic hearing loss 20, Baraitser-winter syndrome 2.

## Similar variants {#similar}

Related ACTG1 variant pages (same residue, condition, or type): [ACTG1 p.Ser233=](/variant/actg1-p-ser233), [ACTG1 p.Ala135Val](/variant/actg1-p-ala135val), [ACTG1 p.Ala204Gly](/variant/actg1-p-ala204gly), [ACTG1 p.Arg183Gln](/variant/actg1-p-arg183gln), [ACTG1 p.Arg183Trp](/variant/actg1-p-arg183trp), [ACTG1 p.Arg206Gln](/variant/actg1-p-arg206gln), [ACTG1 p.Arg210Cys](/variant/actg1-p-arg210cys), [ACTG1 p.Arg254Trp](/variant/actg1-p-arg254trp).

### 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 2924802). 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.*