Is DOCK6 p.Val45Ile (c.133G>A) pathogenic?

DOCK6 p.Val45Ile (c.133G>A) is classified Conflicting classifications of pathogenicity in DOCK6 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0978); Rare (popmax 0.287%, sas); Associated with intellectual disability.

What condition is associated with DOCK6 p.Val45Ile (c.133G>A)?

DOCK6 p.Val45Ile (c.133G>A) is associated with intellectual disability, bone Paget disease (ClinVar).

How common is DOCK6 p.Val45Ile (c.133G>A) in the general population?

DOCK6 p.Val45Ile (c.133G>A) is rare (popmax 0.287%, sas) (gnomAD).

What do computational predictors say about DOCK6 p.Val45Ile (c.133G>A)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

DOCK6 p.Val45Ile

c.133G>A · rs183060698 · VCV710944

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.287%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	24.2	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 0.287% South Asian · 256/89,248 alleles

Filtering AF 0.258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.247%

Overall 0.201% 3,225/1,602,672 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.509%	196
South Asiangrpmax	0.287%	349
European (non-Finnish)	0.221%	452
Remaining individualsnot grpmax-eligible	0.198%	505
Admixed American	0.083%	1,206
Finnishnot grpmax-eligible	0.0411%	2,433
Middle Eastern	0.0331%	3,023
African / African-American	0.0281%	3,562
East Asian	0.00225%	44,408

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val45Ile
Coding: c.133G>A
MANE Select: NM_020812
dbSNP: rs183060698
Type: single nucleotide variant
Location: chr19:11252958 (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

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: bone Paget disease

Similar variants

DOCK6 p.Val45Leu Uncertain significance ★ ⚠ same residue
DOCK6 p.Asn1557Lys Uncertain significance ★★ ⚠ same condition
DOCK6 p.His1739Leu Uncertain significance ★★ ⚠ same condition
DOCK6 c.2160+5G>A Benign/Likely benign ★★ same condition
DOCK6 p.Arg1354Gln Uncertain significance ★ ⚠ same condition
DOCK6 p.Thr1897Met Uncertain significance ★ ⚠ same condition
DOCK6 p.Arg63Gln Likely benign same condition
DOCK6 p.His631Tyr Likely benign 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-val45ile (accessed [today's date]).

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