# NM_203447.4(DOCK8):c.324G>A (p.Pro108=)

https://sugi.bio/variant/dock8-p-pro108

## Summary

**DOCK8 p.Pro108= (c.324G>A)** is classified **Likely benign** in DOCK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). Ultra-rare (popmax 0.0164%, mid); Associated with combined immunodeficiency due to DOCK8 deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs769338643 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the DOCK8 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to combined immunodeficiency due to DOCK8 deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DOCK8 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Combined immunodeficiency due to DOCK8 deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Chronic otitis media — Very frequent (99-80%)
- Atopic dermatitis — Very frequent (99-80%)
- Pneumonia — Very frequent (99-80%)
- Asthma — Very frequent (99-80%)
- Recurrent respiratory infections — Very frequent (99-80%)
- Increased circulating IgE level — Very frequent (99-80%)
- Recurrent viral infections — Very frequent (99-80%)
- Recurrent candida infections — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002816/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOCK8](https://sugi.bio/atlas/gene/DOCK8/) |
| Protein change (HGVS p.) | p.Pro108= |
| Coding change (HGVS c.) | c.324G>A |
| MANE Select transcript | [NM_203447](https://www.ncbi.nlm.nih.gov/nuccore/NM_203447) |
| dbSNP | [rs769338643](https://www.ncbi.nlm.nih.gov/snp/rs769338643/) |
| Variant type | single nucleotide variant |
| Location | chr9:286628-286628 (GRCh38) |
| ClinVar | [VCV1991258](https://www.ncbi.nlm.nih.gov/clinvar/variation/1991258/) |

**All HGVS expressions:** `LRG_196:g.76764G>A`, `LRG_196t1:c.324G>A`, `NC_000009.11:g.286628G>A`, `NC_000009.12:g.286628G>A`, `NG_017007.1:g.76764G>A`, `NG_085052.1:g.934G>A`, `NM_001190458.2:c.120G>A`, `NM_001193536.2:c.120G>A`, `NM_203447.4:c.324G>A`

## 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 -3.84, GERP -4.79 — fast-evolving / accelerated position
- CADD: **PHRED 12.41**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, 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 **0.0164%** (mid) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/6,080 in the highest group · 9/1,613,680 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,080 |
| Finnish (not grpmax-eligible) | 0.00625% | 16,002 |
| East Asian | 0.00223% | 44,886 |
| African / African-American | 0.00134% | 74,890 |
| European (non-Finnish) | 0.00017% | 589,911 |

*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}

**DOCK8** population constraint: LOEUF 0.622, pLI 2.9093e-17, missense-Z -1.7115. *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):

- **combined immunodeficiency due to DOCK8 deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.17, 27% of residues very-high.

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

*Describes the biological roles of DOCK8 (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:** DOCK8's established molecular role includes guanyl-nucleotide exchange factor activity.


### Pathways affected {#pathways}

DOCK8 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity.

**Biological process:** positive regulation of GTPase activity, memory T cell proliferation, positive regulation of establishment of T cell polarity, cellular response to chemokine, positive regulation of T cell migration.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-03.

**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 | 2023-10-03 |

## Associated conditions {#conditions}

[combined immunodeficiency due to DOCK8 deficiency](https://sugi.bio/atlas/disease/combined-immunodeficiency-due-to-dock8-deficiency/).

**Reported phenotype names (ClinVar):** Combined immunodeficiency due to DOCK8 deficiency, Hyper-IgE recurrent infection syndrome, autosomal recessive, HIES autosomal recessive, HYPER-IgE SYNDROME 2, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS, DOCK8 Deficiency, HYPER-IgE RECURRENT INFECTION SYNDROME 2, AUTOSOMAL RECESSIVE.

## Similar variants {#similar}

Related DOCK8 variant pages (same residue, condition, or type): [DOCK8 p.Pro108Leu](/variant/dock8-p-pro108leu), [DOCK8 c.1680-2A>G](/variant/dock8-c-1680-minus-2a-g), [DOCK8 c.2779-2A>C](/variant/dock8-c-2779-minus-2a-c), [DOCK8 c.2971-1G>A](/variant/dock8-c-2971-minus-1g-a), [DOCK8 c.3530+1G>A](/variant/dock8-c-3530-plus-1g-a), [DOCK8 c.528+1G>A](/variant/dock8-c-528-plus-1g-a), [DOCK8 c.529-2A>G](/variant/dock8-c-529-minus-2a-g), [DOCK8 p.Arg1388Ter](/variant/dock8-p-arg1388ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1991258). 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.*