Is DOCK6 p.Arg174His (c.521G>A) pathogenic?

DOCK6 p.Arg174His (c.521G>A) is classified Uncertain significance in DOCK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-26). AlphaMissense: likely benign (0.0705); Very rare (popmax 0.00669%, eas); Associated with Adams-Oliver syndrome 2.

What condition is associated with DOCK6 p.Arg174His (c.521G>A)?

DOCK6 p.Arg174His (c.521G>A) is associated with Adams-Oliver syndrome 2 (ClinVar).

How common is DOCK6 p.Arg174His (c.521G>A) in the general population?

DOCK6 p.Arg174His (c.521G>A) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about DOCK6 p.Arg174His (c.521G>A)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

DOCK6 p.Arg174His

c.521G>A · rs746304989 · VCV2440986

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Adams-Oliver syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81	GERP -0.12, phastCons 0.78
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	13.71	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00669% East Asian · 3/44,810 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00106% 17/1,611,134 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,937
South Asian	0.00221%	45,248
Remaining individualsnot grpmax-eligible	0.0016%	62,324
African / African-American	0.00134%	74,892
European (non-Finnish)	0.000848%	117,882

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.Arg174His
Coding: c.521G>A
MANE Select: NM_020812
dbSNP: rs746304989
Type: single nucleotide variant
Location: chr19:11251073 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.78 · 7 PDB
Residue 174: the 'disordered' region

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

Disease context

Adams-Oliver syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOCK6 p.Arg174Cys Uncertain significance ★★ ⚠ same residue
DOCK6 c.5939+2T>C Pathogenic ★★ same condition
DOCK6 c.807-1G>A Likely pathogenic ★★ same condition
DOCK6 p.Arg1526Ter Pathogenic/Likely pathogenic ★★ same condition
DOCK6 p.Arg184Ter Pathogenic/Likely pathogenic ★★ same condition
DOCK6 p.Arg488Ter Pathogenic/Likely pathogenic ★★ same condition
DOCK6 p.Gln1188Ter Pathogenic/Likely pathogenic ★★ same condition
DOCK6 p.Tyr129Ter Pathogenic/Likely 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/dock6-p-arg174his (accessed [today's date]).

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