# NM_005720.4(ARPC1B):c.783G>A (p.Ala261=)

https://sugi.bio/variant/arpc1b-p-ala261

## Summary

**ARPC1B p.Ala261= (c.783G>A)** is classified **Pathogenic** in ARPC1B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-07-05). Very rare (popmax 0.00167%, amr); Associated with platelet abnormalities with eosinophilia and immune-mediated inflammatory disease.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs779597975 · 5 submitters · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ARPC1B gene that is considered disease-causing, submitted by 5 submitters, and is linked to platelet abnormalities with eosinophilia and immune-mediated inflammatory disease.

*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 | [ARPC1B](https://sugi.bio/atlas/gene/ARPC1B/) |
| Protein change (HGVS p.) | p.Ala261= |
| Coding change (HGVS c.) | c.783G>A |
| MANE Select transcript | [NM_005720](https://www.ncbi.nlm.nih.gov/nuccore/NM_005720) |
| dbSNP | [rs779597975](https://www.ncbi.nlm.nih.gov/snp/rs779597975/) |
| Variant type | single nucleotide variant |
| Location | chr7:99391253-99391253 (GRCh38) |
| ClinVar | [VCV1030961](https://www.ncbi.nlm.nih.gov/clinvar/variation/1030961/) |

**All HGVS expressions:** `LRG_1188:g.21579G>A`, `LRG_1188t1:c.783G>A`, `NC_000007.13:g.98988876G>A`, `NC_000007.14:g.99391253G>A`, `NG_055676.1:g.21579G>A`, `NM_005720.4:c.783G>A`

## Computational & population evidence {#evidence}

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

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.83) — consistent with the pathogenic call
- Conservation: phyloP 2.906, GERP -0.85, phastCons 1 — highly conserved position (PP3-type support)
- 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.83**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.83**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.66** (loss), gain 0.02 / loss 0.66. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/59,964 in the highest group · 7/1,613,716 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,240 |
| Admixed American (grpmax) | 0.00167% | 59,964 |
| European (non-Finnish) | 0.000339% | 294,989 |

Remaining individuals 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}

**ARPC1B** population constraint: LOEUF 0.876, pLI 1.063e-06, missense-Z 0.86139. *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):

- **platelet abnormalities with eosinophilia and immune-mediated inflammatory disease** — Definitive (AR)

## Protein context {#protein}

Residue **261** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 92.81, 86% of residues very-high.

**4 experimental structure(s)** (PDB): [6UHC](https://www.rcsb.org/structure/6UHC), [6YW6](https://www.rcsb.org/structure/6YW6), [8P94](https://www.rcsb.org/structure/8P94), [9I2B](https://www.rcsb.org/structure/9I2B).

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

*Describes the biological roles of ARPC1B (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:** ARPC1B's established molecular role includes structural constituent of cytoskeleton. In Reactome, ARPC1B is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** ARPC1B loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

ARPC1B participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | curated |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | electronic |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | electronic |

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

**Molecular function:** structural constituent of cytoskeleton.

**Biological process:** Arp2/3 complex-mediated actin nucleation.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-05.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 5 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-01 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-12 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-05 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-13 |

## Associated conditions {#conditions}

[platelet abnormalities with eosinophilia and immune-mediated inflammatory disease](https://sugi.bio/atlas/disease/platelet-abnormalities-with-eosinophilia-and-immune-mediated-inflammatory-disease/).

**Reported phenotype names (ClinVar):** Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, not provided, Squamous cell carcinoma of the head and neck, IMMUNODEFICIENCY 71 WITH INFLAMMATORY DISEASE AND CONGENITAL THROMBOCYTOPENIA, none provided.

## Similar variants {#similar}

Related ARPC1B variant pages (same residue, condition, or type): [ARPC1B p.Ala261Val](/variant/arpc1b-p-ala261val), [ARPC1B p.Ala261Ser](/variant/arpc1b-p-ala261ser), [ARPC1B c.64+2T>A](/variant/arpc1b-c-64-plus-2t-a), [ARPC1B p.Ala238Val](/variant/arpc1b-p-ala238val), [ARPC1B p.Arg103His](/variant/arpc1b-p-arg103his), [ARPC1B p.Cys162Gly](/variant/arpc1b-p-cys162gly), [ARPC1B p.Gly39Ser](/variant/arpc1b-p-gly39ser), [ARPC1B p.Met350Arg](/variant/arpc1b-p-met350arg).

### 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 1030961). 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.*