# NM_005720.4(ARPC1B):c.696C>G (p.Asp232Glu)

https://sugi.bio/variant/arpc1b-p-asp232glu

## Summary

**ARPC1B p.Asp232Glu (c.696C>G)** is classified **Likely benign** in ARPC1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0639); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the ARPC1B gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Asp232Glu |
| Coding change (HGVS c.) | c.696C>G |
| MANE Select transcript | [NM_005720](https://www.ncbi.nlm.nih.gov/nuccore/NM_005720) |
| Variant type | single nucleotide variant |
| Location | chr7:99391088-99391088 (GRCh38) |
| ClinVar | [VCV4585462](https://www.ncbi.nlm.nih.gov/clinvar/variation/4585462/) |

**All HGVS expressions:** `LRG_1188:g.21414C>G`, `LRG_1188t1:c.696C>G`, `NC_000007.13:g.98988711C>G`, `NC_000007.14:g.99391088C>G`, `NG_055676.1:g.21414C>G`, `NM_005720.4:c.696C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0639)
- REVEL 0.078 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.279 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.61, GERP -3.74 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.231**. 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 0.89** across the covering region of the MANE Select transcript (99,385,715–99,394,486), spanning 8,771 bp. Chi-square p 0.0087. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.20 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,702 in the highest group · 6/1,461,198 alleles overall — very rare (popmax 0.000339%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,241 |
| European (non-Finnish) (grpmax) | 0.000339% | 294,925 |

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 **232** lies in a turn.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-09.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-09 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related ARPC1B variant pages (same residue, condition, or type): [ARPC1B p.Asp232Asn](/variant/arpc1b-p-asp232asn), [ARPC1B p.Ala275Thr](/variant/arpc1b-p-ala275thr), [ARPC1B p.Ala276Thr](/variant/arpc1b-p-ala276thr), [ARPC1B p.Arg142Cys](/variant/arpc1b-p-arg142cys), [ARPC1B p.Arg167Trp](/variant/arpc1b-p-arg167trp), [ARPC1B p.Arg216Cys](/variant/arpc1b-p-arg216cys), [ARPC1B p.Asn109Lys](/variant/arpc1b-p-asn109lys), [ARPC1B p.Asn327Ser](/variant/arpc1b-p-asn327ser).

### 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 4585462). 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.*