# NM_016188.5(ACTL6B):c.1027G>A (p.Gly343Arg)

https://sugi.bio/variant/actl6b-p-gly343arg

## Summary

**ACTL6B p.Gly343Arg (c.1027G>A)** is classified **Pathogenic/Likely pathogenic** in ACTL6B (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-06-29). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1; Associated with ACTL6B-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1131692228 · 18 submitters · 4 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ACTL6B gene that is considered likely disease-causing, submitted by 18 submitters, and is linked to ACTL6B-related disorder.

*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 | [ACTL6B](https://sugi.bio/atlas/gene/ACTL6B/) |
| Protein change (HGVS p.) | p.Gly343Arg |
| Coding change (HGVS c.) | c.1027G>A |
| MANE Select transcript | [NM_016188](https://www.ncbi.nlm.nih.gov/nuccore/NM_016188) |
| dbSNP | [rs1131692228](https://www.ncbi.nlm.nih.gov/snp/rs1131692228/) |
| Variant type | single nucleotide variant |
| Location | chr7:100646637-100646637 (GRCh38) |
| ClinVar | [VCV430804](https://www.ncbi.nlm.nih.gov/clinvar/variation/430804/) |

**All HGVS expressions:** `NC_000007.13:g.100244260C>T`, `NC_000007.14:g.100646637C>T`, `NM_016188.5:c.1027G>A`, `NR_134539.2:n.1121G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9934) — concordant with the pathogenic call
- REVEL 0.761 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.582 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor gain** (Δ 0.37) — consistent with the pathogenic call
- Conservation: phyloP 7.682, GERP 4.9, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.60** across the covering region of the MANE Select transcript (100,643,249–100,646,772), spanning 3,523 bp. Chi-square p 8.1e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.37**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.37**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **343** lies in a UniProt-annotated variant site (in dee76); a UniProt-annotated variant site (in iddssad; probable gain-of-function mutation).

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-29.

**Submitter consensus:** conflicting (13 Pathogenic, 4 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 18 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2019-06-19 |
| HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Pathogenic | criteria provided, single submitter | research | 2019-06-27 |
| CHU Sainte-Justine Research Center, University of Montreal | Likely pathogenic | no assertion criteria provided | research | 2019-03-01 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-06-10 |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-01 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-07-23 |
| Laboratory of Medical Genetics, University of Torino | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-29 |
| SIB Swiss Institute of Bioinformatics | Likely pathogenic | criteria provided, single submitter | curation | 2019-07-28 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Uncertain significance | flagged submission | clinical testing | 2018-11-30 |
| Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2021-09-15 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Molecular Genetics laboratory, Necker Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2023-01-20 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-28 |
| Solve-RD Consortium | Likely pathogenic | no assertion criteria provided | provider interpretation | 2022-06-01 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2022-06-24 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-03 |

## Associated conditions {#conditions}

[ACTL6B-related disorder](https://sugi.bio/atlas/disease/actl6b-related-disorder/), [intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/), [autism](https://sugi.bio/atlas/disease/autism/), [intellectual developmental disorder with severe speech and ambulation defects](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-with-severe-speech-and-ambulation-defects/).

**Reported phenotype names (ClinVar):** ACTL6B-related disorder, ACTL6B-related dominant intellectual disability, Autism, Intellectual developmental disorder with severe speech and ambulation defects, not provided, Intellectual disability, ACTL6B-related BAFopathy, Inborn genetic diseases, Autistic disorder of childhood onset, Autistic disorder.

## Same-residue context {#hotspot}

Residue **343** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ACTL6B p.Gly343Trp](/variant/actl6b-p-gly343trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ACTL6B variant pages (same residue, condition, or type): [ACTL6B p.Gly343Trp](/variant/actl6b-p-gly343trp), [ACTL6B p.Arg97Ter](/variant/actl6b-p-arg97ter), [ACTL6B p.Arg363Gln](/variant/actl6b-p-arg363gln), [ACTL6B p.Val421Met](/variant/actl6b-p-val421met), [ACTL6B c.*98T>A](/variant/actl6b-c-star-98t-a), [ACTL6B c.103-1G>C](/variant/actl6b-c-103-minus-1g-c), [ACTL6B p.Arg298Gln](/variant/actl6b-p-arg298gln), [ACTL6B p.Asn125Lys](/variant/actl6b-p-asn125lys).

### 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 430804). 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.*