Is DOCK4 p.Lys1059Arg (c.3176A>G) pathogenic?

DOCK4 p.Lys1059Arg (c.3176A>G) is classified Conflicting classifications of pathogenicity in DOCK4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-06-01). AlphaMissense: ambiguous (0.5027); Ultra-rare (popmax 0.0336%, amr).

How common is DOCK4 p.Lys1059Arg (c.3176A>G) in the general population?

DOCK4 p.Lys1059Arg (c.3176A>G) is ultra-rare (popmax 0.0336%, amr) (gnomAD).

What do computational predictors say about DOCK4 p.Lys1059Arg (c.3176A>G)?

AlphaMissense predicts ambiguous (score 0.5027) — an in-silico prediction, not a clinical call.

DOCK4 p.Lys1059Arg

c.3176A>G · rs199775424 · VCV2373392

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, amr)

Computational evidence

Protein change
AlphaMissense	0.5027	ambiguous
REVEL	0.595	indeterminate
SaProt	LLR -3.68	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 465 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	26.0	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 0.0336% Admixed American · 20/59,612 alleles

Filtering AF 0.0222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0185%

Overall 0.0114% 184/1,612,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0336%	2,981
Ashkenazi Jewishnot grpmax-eligible	0.0305%	3,275
Middle Eastern	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.0144%	6,935
European (non-Finnish)	0.012%	8,363
Finnishnot grpmax-eligible	0.00313%	31,994
African / African-American	0.00267%	37,485

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: DOCK4
Protein: p.Lys1059Arg
Coding: c.3176A>G
MANE Select: NM_001363540
dbSNP: rs199775424
Type: single nucleotide variant
Location: chr7:111790596 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.47
Residue 1059: a UniProt-annotated variant site (found in a cns cancer cell line)

Full DOCK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOCK4 p.Arg490Trp Uncertain significance ★★ ⚠ same type
DOCK4 p.Gln1223Arg Uncertain significance ★★ ⚠ same type
DOCK4 p.His1716Tyr Uncertain significance ★★ ⚠ same type
DOCK4 p.Pro1641Leu Uncertain significance ★★ ⚠ same type
DOCK4 p.Ser750Arg Uncertain significance ★★ ⚠ same type
DOCK4 c.550-8T>C Benign/Likely benign ★★ same type
DOCK4 p.Arg106Cys Benign/Likely benign ★★ ⚠ same type
DOCK4 p.Arg106His Benign/Likely benign ★★ 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/dock4-p-lys1059arg (accessed [today's date]).

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