Is DOCK2 p.Arg1449Cys (c.4345C>T) pathogenic?

DOCK2 p.Arg1449Cys (c.4345C>T) is classified Uncertain significance in DOCK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: ambiguous (0.5285); Very rare (popmax 0.00305%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DOCK2 p.Arg1449Cys (c.4345C>T)?

DOCK2 p.Arg1449Cys (c.4345C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DOCK2 p.Arg1449Cys (c.4345C>T) in the general population?

DOCK2 p.Arg1449Cys (c.4345C>T) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about DOCK2 p.Arg1449Cys (c.4345C>T)?

AlphaMissense predicts ambiguous (score 0.5285) — an in-silico prediction, not a clinical call.

DOCK2 p.Arg1449Cys

c.4345C>T · VCV3273314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5285	ambiguous
REVEL	0.282	benign-leaning
SaProt	LLR -11.12	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 33 kb · p 0.0025 · regional, not allelic
Overall
CADD	27.7	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 0.00305% European (non-Finnish) · 36/1,179,950 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00235% 38/1,613,896 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00305%	32,776
African / African-American	0.00267%	37,432

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.Arg1449Cys
Coding: c.4345C>T
MANE Select: NM_004946
Type: single nucleotide variant
Location: chr5:170056733 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 1449: the docker domain; the 'interaction with crkl' region; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOCK2 p.Arg1449His Uncertain significance ★ ⚠ same residue
DOCK2 p.Ala1765Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala812Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1071Cys Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg11Gln Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1200His Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1274Gln Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1480Cys 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-arg1449cys (accessed [today's date]).

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