Is DOCK2 p.Tyr45Cys (c.134A>G) pathogenic?

DOCK2 p.Tyr45Cys (c.134A>G) is classified Uncertain significance in DOCK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-08). AlphaMissense: ambiguous (0.5108); Ultra-rare (popmax 0.0538%, sas); Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Tyr45Cys (c.134A>G)?

DOCK2 p.Tyr45Cys (c.134A>G) is associated with DOCK2 deficiency (ClinVar).

How common is DOCK2 p.Tyr45Cys (c.134A>G) in the general population?

DOCK2 p.Tyr45Cys (c.134A>G) is ultra-rare (popmax 0.0538%, sas) (gnomAD).

What do computational predictors say about DOCK2 p.Tyr45Cys (c.134A>G)?

AlphaMissense predicts ambiguous (score 0.5108) — an in-silico prediction, not a clinical call.

DOCK2 p.Tyr45Cys

Q: How is Combined immunodeficiency due to DOCK2 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.134A>G · rs150182906 · VCV1415984

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5108 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0538%, sas)

Conditions

DOCK2 deficiency

Computational evidence

Protein change
AlphaMissense	0.5108	ambiguous
REVEL	0.454	indeterminate
SaProt	LLR -9.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.17, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 63 kb · p 1.8e-09 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0538% South Asian · 49/91,078 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0375%

Overall 0.00458% 74/1,614,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0538%	1,859
African / African-American	0.0173%	5,774
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	0.000847%	117,999

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DOCK2
Protein: p.Tyr45Cys
Coding: c.134A>G
MANE Select: NM_004946
dbSNP: rs150182906
Type: single nucleotide variant
Location: chr5:169669294 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 45: the sh3 domain; a β-strand

Full DOCK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DOCK2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to DOCK2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

INSYN2B p.Thr45Ile Uncertain significance ★ ⚠ same residue
DOCK2 c.2267+3G>A Uncertain significance ★★ same condition
DOCK2 c.2704-3C>T Uncertain significance ★★ same condition
DOCK2 c.4467+4A>G Uncertain significance ★★ same condition
DOCK2 p.Ala1393Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala1710Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala1765Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala24Pro Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dock2-p-tyr45cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown