Is DOCK6 p.Phe727Leu (c.2181C>A) pathogenic?

DOCK6 p.Phe727Leu (c.2181C>A) is classified Uncertain significance in DOCK6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely pathogenic (0.9864); Very rare (popmax 0.00248%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DOCK6 p.Phe727Leu (c.2181C>A)?

DOCK6 p.Phe727Leu (c.2181C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DOCK6 p.Phe727Leu (c.2181C>A) in the general population?

DOCK6 p.Phe727Leu (c.2181C>A) is very rare (popmax 0.00248%, nfe) (gnomAD).

What do computational predictors say about DOCK6 p.Phe727Leu (c.2181C>A)?

AlphaMissense predicts likely pathogenic (score 0.9864) — an in-silico prediction, not a clinical call.

DOCK6 p.Phe727Leu

c.2181C>A · rs773582745 · VCV3085065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00248%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9864	likely pathogenic · top 5% in DOCK6
REVEL	0.479	indeterminate
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.1, 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 0.00248% European (non-Finnish) · 29/1,171,620 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0015%

Overall 0.00207% 33/1,595,750 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00485%	20,631
European (non-Finnish)grpmax	0.00248%	40,401
African / African-American	0.00134%	74,686

Remaining individuals 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.Phe727Leu
Coding: c.2181C>A
MANE Select: NM_020812
dbSNP: rs773582745
Type: single nucleotide variant
Location: chr19:11236557 (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

Similar variants

DOCK6 c.5939+2T>C Pathogenic ★★ same condition
DOCK6 p.Glu1494Ter Pathogenic ★★ same condition
DOCK6 p.Ala1153Thr Uncertain significance ★★ ⚠ same condition
DOCK6 p.Ala1207Val Uncertain significance ★★ ⚠ same condition
DOCK6 p.Ala1241Thr Uncertain significance ★★ ⚠ same condition
DOCK6 p.Ala1319Val Uncertain significance ★★ ⚠ same condition
DOCK6 p.Ala133Thr Uncertain significance ★★ ⚠ same condition
DOCK6 p.Ala1481Thr Uncertain significance ★★ ⚠ 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-phe727leu (accessed [today's date]).

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