Is DOCK3 p.Arg741Trp (c.2221C>T) pathogenic?

DOCK3 p.Arg741Trp (c.2221C>T) is classified Uncertain significance in DOCK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely pathogenic (0.9748); Very rare (popmax 0.0011%, sas); Associated with neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia.

How common is DOCK3 p.Arg741Trp (c.2221C>T) in the general population?

DOCK3 p.Arg741Trp (c.2221C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DOCK3 p.Arg741Trp (c.2221C>T)?

AlphaMissense predicts likely pathogenic (score 0.9748) — an in-silico prediction, not a clinical call.

DOCK3 p.Arg741Trp

Q: What condition is associated with DOCK3 p.Arg741Trp (c.2221C>T)?

DOCK3 p.Arg741Trp (c.2221C>T) is associated with neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia (ClinVar).

c.2221C>T · rs753075056 · VCV2573088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia

Computational evidence

Protein change
AlphaMissense	0.9748	likely pathogenic
REVEL	0.713	pathogenic-leaning
SaProt	LLR -11.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP -0.085, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 154 kb · p 4e-32 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,042 alleles

Overall 0.000137% 2/1,461,534 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,042
European (non-Finnish)	8.48e-05%	1,179,793

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.Arg741Trp
Coding: c.2221C>T
MANE Select: NM_004947
dbSNP: rs753075056
Type: single nucleotide variant
Location: chr3:51260192 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.52
Residue 741: a UniProt-annotated variant site (in nedidha)

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

Disease context

neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOCK3 p.Arg392Gln Uncertain significance ★★ ⚠ same condition
DOCK3 p.Lys1296Arg Uncertain significance ★★ ⚠ same condition
DOCK3 p.Val148Met Uncertain significance ★★ ⚠ same condition
DOCK3 p.Val668Met Uncertain significance ★★ ⚠ same condition
DOCK3 c.1918-3T>C Benign ★★ same condition
DOCK3 c.1038-2A>G Likely pathogenic ★ same condition
DOCK3 p.Arg2001Ter Likely pathogenic ★ same condition
DOCK3 p.Gln128Ter Pathogenic ★ 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/dock3-p-arg741trp (accessed [today's date]).

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