Is DOCK6 p.Pro250Leu (c.749C>T) pathogenic?

DOCK6 p.Pro250Leu (c.749C>T) is classified Benign in DOCK6 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2847); Common (popmax 76.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Adams-Oliver syndrome 2.

What condition is associated with DOCK6 p.Pro250Leu (c.749C>T)?

DOCK6 p.Pro250Leu (c.749C>T) is associated with Adams-Oliver syndrome 2 (ClinVar).

What do computational predictors say about DOCK6 p.Pro250Leu (c.749C>T)?

AlphaMissense predicts likely benign (score 0.2847) — an in-silico prediction, not a clinical call.

DOCK6 p.Pro250Leu

Q: How common is DOCK6 p.Pro250Leu (c.749C>T) in the general population?

DOCK6 p.Pro250Leu (c.749C>T) is common (popmax 76.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.749C>T · rs12978266 · VCV261359

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2847 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 76.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Adams-Oliver syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2847	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -3.54	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 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	24.7	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 76.2% Middle Eastern · 4,608/6,050 alleles

Filtering AF 74.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 73.6%

Overall 67.1% 1,080,653/1,610,060 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	76.2%	1
Middle Easterngrpmax	76.2%	1
Amishnot grpmax-eligible	75.2%	1
South Asian	71.8%	1
European (non-Finnish)	70.5%	1
Remaining individualsnot grpmax-eligible	66.7%	1
Finnishnot grpmax-eligible	66.5%	2
Admixed American	58.5%	2
East Asian	52.7%	2
African / African-American	19.5%	5

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.Pro250Leu
Coding: c.749C>T
MANE Select: NM_020812
dbSNP: rs12978266
Type: single nucleotide variant
Location: chr19:11248123 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.78 · 7 PDB
Residue 250: a UniProt-annotated variant site (in); 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 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
DOCK6 p.Tyr235Ter 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-pro250leu (accessed [today's date]).

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