Is DOCK3 p.Arg140Leu (c.419G>T) pathogenic?

DOCK3 p.Arg140Leu (c.419G>T) is classified Uncertain significance in DOCK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-16). AlphaMissense: ambiguous (0.4783); Very rare (popmax 0.000424%, nfe).

How common is DOCK3 p.Arg140Leu (c.419G>T) in the general population?

DOCK3 p.Arg140Leu (c.419G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about DOCK3 p.Arg140Leu (c.419G>T)?

AlphaMissense predicts ambiguous (score 0.4783) — an in-silico prediction, not a clinical call.

DOCK3 p.Arg140Leu

c.419G>T · VCV4529699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4783	ambiguous
REVEL	0.279	benign-leaning
SaProt	LLR -4.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 550 kb · p 0.00035 · regional, not allelic
Overall
CADD	24.5	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 0.000424% European (non-Finnish) · 5/1,179,850 alleles

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

Overall 0.000342% 5/1,461,662 alleles · very rare

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.Arg140Leu
Coding: c.419G>T
MANE Select: NM_004947
Type: single nucleotide variant
Location: chr3:51064551 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.52
Residue 140: 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.Arg140Trp 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-arg140leu (accessed [today's date]).

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