Is DOCK2 p.Ile980Thr (c.2939T>C) pathogenic?

DOCK2 p.Ile980Thr (c.2939T>C) is classified Conflicting classifications of pathogenicity in DOCK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: ambiguous (0.4595); Rare (popmax 0.33%, sas); Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Ile980Thr (c.2939T>C)?

DOCK2 p.Ile980Thr (c.2939T>C) is associated with DOCK2 deficiency (ClinVar).

How common is DOCK2 p.Ile980Thr (c.2939T>C) in the general population?

DOCK2 p.Ile980Thr (c.2939T>C) is rare (popmax 0.33%, sas) (gnomAD).

What do computational predictors say about DOCK2 p.Ile980Thr (c.2939T>C)?

AlphaMissense predicts ambiguous (score 0.4595) — an in-silico prediction, not a clinical call.

DOCK2 p.Ile980Thr

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.2939T>C · rs148694888 · VCV721274

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4595 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.33%, sas)

Conditions

DOCK2 deficiency

Computational evidence

Protein change
AlphaMissense	0.4595	ambiguous
REVEL	0.514	indeterminate
SaProt	LLR -10.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 348 kb · p 3.1e-21 · regional, not allelic
Overall
CADD	26.8	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 0.33% South Asian · 299/90,568 alleles

Filtering AF 0.299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.287%

Overall 0.0798% 1,285/1,610,866 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.33%	303
Middle Eastern	0.232%	431
Ashkenazi Jewishnot grpmax-eligible	0.177%	566
Remaining individualsnot grpmax-eligible	0.0738%	1,355
Admixed American	0.0668%	1,497
European (non-Finnish)	0.0666%	1,501
Finnishnot grpmax-eligible	0.0611%	1,637
African / African-American	0.012%	8,332
East Asian	0.00223%	44,810

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.Ile980Thr
Coding: c.2939T>C
MANE Select: NM_004946
dbSNP: rs148694888
Type: single nucleotide variant
Location: chr5:169985868 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 980: the 'interaction with crkl' region

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

DOCK2 p.Ile980Val 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-ile980thr (accessed [today's date]).

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