# NM_203447.4(DOCK8):c.2295C>T (p.Ser765=)

https://sugi.bio/variant/dock8-p-ser765

## Summary

**DOCK8 p.Ser765= (c.2295C>T)** is classified **Benign** in DOCK8 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). Common (popmax 8.14%, afr) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to DOCK8 deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs12348944 · 8 submitters · 1 linked condition · common (popmax 8.14%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DOCK8 gene that is classified as benign — not considered disease-causing, submitted by 8 submitters, 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.Ser765= |
| Coding change (HGVS c.) | c.2295C>T |
| MANE Select transcript | [NM_203447](https://www.ncbi.nlm.nih.gov/nuccore/NM_203447) |
| dbSNP | [rs12348944](https://www.ncbi.nlm.nih.gov/snp/rs12348944/) |
| Variant type | single nucleotide variant |
| Location | chr9:377066-377066 (GRCh38) |
| ClinVar | [VCV137138](https://www.ncbi.nlm.nih.gov/clinvar/variation/137138/) |

**All HGVS expressions:** `LRG_196:g.167202C>T`, `LRG_196t1:c.2295C>T`, `NC_000009.11:g.377066C>T`, `NC_000009.12:g.377066C>T`, `NG_017007.1:g.167202C>T`, `NM_001190458.2:c.2091C>T`, `NM_001193536.2:c.2091C>T`, `NM_203447.4:c.2295C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 8.14%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -11.314, GERP -4.84 — fast-evolving / accelerated position
- CADD: **PHRED 0.184**. 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: **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 **8.14%** (afr) · FAF95 7.97% · FAF99 7.9% · 6,109/75,028 in the highest group · 22,668/1,613,360 alleles overall — common (popmax 8.14%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 8.14% | 12 |
| Middle Eastern | 1.78% | 56 |
| Admixed American | 1.54% | 65 |
| Remaining individuals (not grpmax-eligible) | 1.48% | 68 |
| European (non-Finnish) | 1.13% | 89 |
| South Asian | 0.941% | 106 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.517% | 193 |
| Finnish (not grpmax-eligible) | 0.43% | 233 |
| Amish (not grpmax-eligible) | 0.219% | 456 |
| East Asian | 0.0201% | 4,987 |

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** unanimous (7/7 Benign).

**Submission history:** 20 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-03-20 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2013-02-21 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2020-03-23 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

## 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, not specified, not provided, Ovarian serous cystadenocarcinoma, Hepatocellular carcinoma, Acute myeloid leukemia, Nonpapillary renal cell carcinoma, Uterine corpus endometrial carcinoma, Colon adenocarcinoma, Sarcoma.

## Similar variants {#similar}

Related DOCK8 variant pages (same residue, condition, or type): [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), [DOCK8 p.Arg1796Ter](/variant/dock8-p-arg1796ter).

### 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 137138). 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.*