Is DOCK6 p.Ser1406Ala (c.4216T>G) pathogenic?

DOCK6 p.Ser1406Ala (c.4216T>G) is classified Uncertain significance in DOCK6 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0966); Rare (popmax 0.165%, mid); Associated with Inborn genetic diseases.

What condition is associated with DOCK6 p.Ser1406Ala (c.4216T>G)?

DOCK6 p.Ser1406Ala (c.4216T>G) is associated with Inborn genetic diseases, Adams-Oliver syndrome 2 (ClinVar).

How common is DOCK6 p.Ser1406Ala (c.4216T>G) in the general population?

DOCK6 p.Ser1406Ala (c.4216T>G) is rare (popmax 0.165%, mid) (gnomAD).

What do computational predictors say about DOCK6 p.Ser1406Ala (c.4216T>G)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

DOCK6 p.Ser1406Ala

c.4216T>G · rs34479977 · VCV235741

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.93	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 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	21.3	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 0.165% Middle Eastern · 10/6,062 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0142% 229/1,613,764 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
African / African-American	0.0746%	1,340
Admixed American	0.0717%	1,395
Remaining individualsnot grpmax-eligible	0.0336%	2,975
European (non-Finnish)	0.0078%	12,825
South Asian	0.00549%	18,216
Finnishnot grpmax-eligible	0.00313%	31,907

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.Ser1406Ala
Coding: c.4216T>G
MANE Select: NM_020812
dbSNP: rs34479977
Type: single nucleotide variant
Location: chr19:11214397 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.78 · 7 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Adams-Oliver syndrome 2

Similar variants

DOCK6 p.Ser1406= Likely benign ★ 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.Glu1494Ter 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-ser1406ala (accessed [today's date]).

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