Is DOCK3 p.Arg746Gly (c.2236C>G) pathogenic?

DOCK3 p.Arg746Gly (c.2236C>G) is classified Uncertain significance in DOCK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-14). AlphaMissense: likely pathogenic (0.6678); Ultra-rare (popmax 0.0164%, mid).

How common is DOCK3 p.Arg746Gly (c.2236C>G) in the general population?

DOCK3 p.Arg746Gly (c.2236C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DOCK3 p.Arg746Gly (c.2236C>G)?

AlphaMissense predicts likely pathogenic (score 0.6678) — an in-silico prediction, not a clinical call.

DOCK3 p.Arg746Gly

c.2236C>G · VCV4529710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6678	likely pathogenic
REVEL	0.413	indeterminate
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.1, phastCons 0.63
Regional constraint	o/e 0.73	unconstrained · MANE · 154 kb · p 4e-32 · regional, not allelic
Overall
CADD	20.8	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,644 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00167%	59,942
European (non-Finnish)	0.000424%	235,973

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: DOCK3
Protein: p.Arg746Gly
Coding: c.2236C>G
MANE Select: NM_004947
Type: single nucleotide variant
Location: chr3:51260207 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.52
Residue 746: a UniProt-annotated variant site (in nedidha)

Full DOCK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOCK3 p.Arg746Gln Uncertain significance ★ ⚠ same residue
DOCK3 p.Arg1609Trp Uncertain significance ★★ ⚠ same type
DOCK3 p.Arg1787Gln Uncertain significance ★★ ⚠ same type
DOCK3 p.Arg2020Cys Uncertain significance ★★ ⚠ same type
DOCK3 p.Arg392Gln Uncertain significance ★★ ⚠ same type
DOCK3 p.Arg486His Uncertain significance ★★ ⚠ same type
DOCK3 p.Gly1699Cys Uncertain significance ★★ ⚠ same type
DOCK3 p.Leu1982Arg Uncertain significance ★★ ⚠ same type

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/dock3-p-arg746gly (accessed [today's date]).

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