# NM_004946.3(DOCK2):c.90G>C (p.Gln30His)

https://sugi.bio/variant/dock2-p-gln30his

## Summary

**DOCK2 p.Gln30His (c.90G>C)** is classified **Conflicting classifications of pathogenicity** in DOCK2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1664); Rare (popmax 0.776%, mid); Associated with DOCK2 deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs141894939 · 9 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.776%, mid)

## For patients & families {#patients}

This is a change in the DOCK2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to DOCK2 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 |
| Diagnostic panels | DOCK2 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012653/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOCK2](https://sugi.bio/atlas/gene/DOCK2/) |
| Protein change (HGVS p.) | p.Gln30His |
| Coding change (HGVS c.) | c.90G>C |
| MANE Select transcript | [NM_004946](https://www.ncbi.nlm.nih.gov/nuccore/NM_004946) |
| dbSNP | [rs141894939](https://www.ncbi.nlm.nih.gov/snp/rs141894939/) |
| Variant type | single nucleotide variant |
| Location | chr5:169654449-169654449 (GRCh38) |
| ClinVar | [VCV542623](https://www.ncbi.nlm.nih.gov/clinvar/variation/542623/) |

**All HGVS expressions:** `LRG_1227:g.22203G>C`, `LRG_1227t1:c.90G>C`, `NC_000005.10:g.169654449G>C`, `NC_000005.9:g.169081453G>C`, `NG_051800.1:g.22203G>C`, `NM_004946.3:c.90G>C`, `NR_156756.1:n.142G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1664)
- REVEL 0.106 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.157 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.469, GERP 1.92, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.69**. 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 0.73** across the covering region of the MANE Select transcript (169,637,327–169,700,105), spanning 62,778 bp. Chi-square p 1.8e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.776%** (mid) · FAF95 0.599% · FAF99 0.537% · 47/6,058 in the highest group · 1,791/1,614,204 alleles overall — rare (popmax 0.776%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.776% | 129 |
| African / African-American | 0.489% | 205 |
| Admixed American | 0.363% | 275 |
| Remaining individuals (not grpmax-eligible) | 0.189% | 530 |
| European (non-Finnish) | 0.0873% | 1,146 |
| South Asian | 0.00988% | 10,120 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,044 |

*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}

**DOCK2** population constraint: LOEUF 0.421, pLI 1, missense-Z 4.9199. *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):

- **DOCK2 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **30** lies in the sh3 domain.

AlphaFold model confidence (whole protein): pLDDT 80.40, 44% of residues very-high.

**6 experimental structure(s)** (PDB): [2RQR](https://www.rcsb.org/structure/2RQR), [2YIN](https://www.rcsb.org/structure/2YIN), [3A98](https://www.rcsb.org/structure/3A98), [3B13](https://www.rcsb.org/structure/3B13), [6TGB](https://www.rcsb.org/structure/6TGB), [6TGC](https://www.rcsb.org/structure/6TGC) — incl. mutant structure 3B13.

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

*Describes the biological roles of DOCK2 (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:** DOCK2's established molecular role includes guanyl-nucleotide exchange factor activity. p.Gln30His falls in the sh3 domain. In Reactome, DOCK2 is annotated in disease pathway(s) including **Nef and signal transduction**.

**Disease mechanism (Reactome):** DOCK2 loss or alteration is curated in [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944).

### Pathways affected {#pathways}

DOCK2 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, T cell receptor binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-01.

**Submitter consensus:** conflicting (8 Likely benign, 1 Uncertain significance).

**Submission history:** 9 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-06-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-16 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |

## Associated conditions {#conditions}

[DOCK2 deficiency](https://sugi.bio/atlas/disease/dock2-deficiency/).

**Reported phenotype names (ClinVar):** DOCK2 deficiency, not provided, DOCK2-related disorder, Inborn genetic diseases, not specified, Immunodeficiency 40, AllHighlyPenetrant, none provided, DOCK2-related condition.

## Similar variants {#similar}

Related DOCK2 variant pages (same residue, condition, or type): [INSYN2B p.Arg30His](/variant/insyn2b-p-arg30his), [DOCK2 c.2267+3G>A](/variant/dock2-c-2267-plus-3g-a), [DOCK2 c.2704-3C>T](/variant/dock2-c-2704-minus-3c-t), [DOCK2 c.4467+4A>G](/variant/dock2-c-4467-plus-4a-g), [DOCK2 p.Ala1393Val](/variant/dock2-p-ala1393val), [DOCK2 p.Ala1710Val](/variant/dock2-p-ala1710val), [DOCK2 p.Ala1765Val](/variant/dock2-p-ala1765val), [DOCK2 p.Ala24Pro](/variant/dock2-p-ala24pro).

### 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 542623). 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.*