Is DOCK6 p.Arg227Trp (c.679C>T) pathogenic?

DOCK6 p.Arg227Trp (c.679C>T) is classified Uncertain significance in DOCK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-25). AlphaMissense: likely pathogenic (0.7476); Very rare (popmax 0.00401%, afr).

How common is DOCK6 p.Arg227Trp (c.679C>T) in the general population?

DOCK6 p.Arg227Trp (c.679C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about DOCK6 p.Arg227Trp (c.679C>T)?

AlphaMissense predicts likely pathogenic (score 0.7476) — an in-silico prediction, not a clinical call.

DOCK6 p.Arg227Trp

c.679C>T · rs35928969 · VCV1980585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7476	likely pathogenic
REVEL	0.426	indeterminate
SaProt	LLR -6.25	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 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	29.3	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 0.00401% African / African-American · 3/74,782 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00118% 19/1,605,956 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,927
Admixed American	0.00334%	29,944
Remaining individualsnot grpmax-eligible	0.00161%	62,060
South Asian	0.0011%	90,970
European (non-Finnish)	0.00102%	97,802

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: DOCK6
Protein: p.Arg227Trp
Coding: c.679C>T
MANE Select: NM_020812
dbSNP: rs35928969
Type: single nucleotide variant
Location: chr19:11250915 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.78 · 7 PDB
Residue 227: the 'disordered' region

Full DOCK6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOCK6 p.Arg227Gln Uncertain significance ★ same residue
DOCK6 p.Arg227= Likely benign ★ same residue
DOCK6 c.4491+1G>A Pathogenic ★★ same type
DOCK6 c.5939+2T>C Pathogenic ★★ same type
DOCK6 c.807-1G>A Likely pathogenic ★★ same type
DOCK6 p.Arg1526Ter Pathogenic/Likely pathogenic ★★ same type
DOCK6 p.Arg184Ter Pathogenic/Likely pathogenic ★★ same type
DOCK6 p.Arg488Ter Pathogenic/Likely pathogenic ★★ 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/dock6-p-arg227trp (accessed [today's date]).

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