Is DOCK6 p.Ala133Val (c.398C>T) pathogenic?

DOCK6 p.Ala133Val (c.398C>T) is classified Conflicting classifications of pathogenicity in DOCK6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-20). AlphaMissense: likely benign (0.1132); Ultra-rare (popmax 0.0332%, mid); Associated with Adams-Oliver syndrome 2.

What condition is associated with DOCK6 p.Ala133Val (c.398C>T)?

DOCK6 p.Ala133Val (c.398C>T) is associated with Adams-Oliver syndrome 2 (ClinVar).

How common is DOCK6 p.Ala133Val (c.398C>T) in the general population?

DOCK6 p.Ala133Val (c.398C>T) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about DOCK6 p.Ala133Val (c.398C>T)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

DOCK6 p.Ala133Val

c.398C>T · rs758680661 · VCV1936955

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Adams-Oliver syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.72	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 5	GERP -1.6, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	15.52	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 0.0332% Middle Eastern · 2/6,022 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00112% 16/1,432,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,011
Remaining individualsnot grpmax-eligible	0.00163%	61,484
European (non-Finnish)	0.00112%	89,644

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.Ala133Val
Coding: c.398C>T
MANE Select: NM_020812
dbSNP: rs758680661
Type: single nucleotide variant
Location: chr19:11252228 (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

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

Similar variants

DOCK6 p.Ala133Thr 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-ala133val (accessed [today's date]).

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