Is DOCK6 p.Pro555Leu (c.1664C>T) pathogenic?

DOCK6 p.Pro555Leu (c.1664C>T) is classified Benign in DOCK6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely pathogenic (0.7119); Common (popmax 7.42%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DOCK6 p.Pro555Leu (c.1664C>T)?

AlphaMissense predicts likely pathogenic (score 0.7119) — an in-silico prediction, not a clinical call.

DOCK6 p.Pro555Leu

Q: How common is DOCK6 p.Pro555Leu (c.1664C>T) in the general population?

DOCK6 p.Pro555Leu (c.1664C>T) is common (popmax 7.42%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1664C>T · rs12609039 · VCV1168291

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7119 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.42%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7119	likely pathogenic
REVEL	0.416	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.51	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 63 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	27.5	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 7.42% European (non-Finnish) · 87,385/1,178,444 alleles

Filtering AF 7.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.36%

Overall 6.86% 110,407/1,610,386 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	8.46%	12
European (non-Finnish)grpmax	7.42%	13
Remaining individualsnot grpmax-eligible	6.94%	14
Finnishnot grpmax-eligible	6.8%	15
South Asian	6.53%	15
East Asian	6.49%	15
Middle Eastern	4.75%	21
Admixed American	2.99%	33
Amishnot grpmax-eligible	2.52%	40
African / African-American	1.32%	76

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.Pro555Leu
Coding: c.1664C>T
MANE Select: NM_020812
dbSNP: rs12609039
Type: single nucleotide variant
Location: chr19:11238284 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.78 · 7 PDB
Residue 555: the c2 dock-type domain; a UniProt-annotated variant site (in)

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

Similar variants

DOCK6 p.Pro555Thr Uncertain significance ★ ⚠ same residue
DOCK6 p.Pro555= Likely benign ★ same residue
DOCK6 c.4491+1G>A Pathogenic ★★ same type
DOCK6 c.5939+2T>C Pathogenic ★★ same type
DOCK6 c.807-1G>A Likely pathogenic ★★ same type
DOCK6 p.Arg1526Ter Pathogenic/Likely pathogenic ★★ same type
DOCK6 p.Arg184Ter Pathogenic/Likely pathogenic ★★ same type
DOCK6 p.Arg488Ter Pathogenic/Likely pathogenic ★★ same type

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-pro555leu (accessed [today's date]).

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