Is DOK6 p.Leu21Phe (c.61C>T) pathogenic?

DOK6 p.Leu21Phe (c.61C>T) is classified Uncertain significance in DOK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-27). AlphaMissense: likely pathogenic (0.9485); Very rare (popmax 0.00246%, eas).

How common is DOK6 p.Leu21Phe (c.61C>T) in the general population?

DOK6 p.Leu21Phe (c.61C>T) is very rare (popmax 0.00246%, eas) (gnomAD).

What do computational predictors say about DOK6 p.Leu21Phe (c.61C>T)?

AlphaMissense predicts likely pathogenic (score 0.9485) — an in-silico prediction, not a clinical call.

DOK6 p.Leu21Phe

c.61C>T · rs201712085 · VCV2588329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9485	likely pathogenic
REVEL	0.344	indeterminate
SaProt	LLR -9.16	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 7.1	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 338 kb · p 0.0011 · regional, not allelic
Overall
CADD	25.5	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 0.00246% East Asian · 1/40,720 alleles

Filtering AF 0.000186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.00261% 41/1,573,778 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.103%	974
Remaining individualsnot grpmax-eligible	0.0066%	15,149
East Asiangrpmax	0.00246%	40,720
South Asian	0.00116%	86,540
European (non-Finnish)	0.000517%	193,424

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: DOK6
Protein: p.Leu21Phe
Coding: c.61C>T
MANE Select: NM_152721
dbSNP: rs201712085
Type: single nucleotide variant
Location: chr18:69401305 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 74.63
Residue 21: the ph domain

Full DOK6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOK6 p.Ala129Ser Uncertain significance ★ same type
DOK6 p.Ala226Val Uncertain significance ★ ⚠ same type
DOK6 p.Ala267Thr Uncertain significance ★ ⚠ same type
DOK6 p.Ala304Ser Uncertain significance ★ ⚠ same type
DOK6 p.Arg19Lys Uncertain significance ★ ⚠ same type
DOK6 p.Arg246Gln Uncertain significance ★ ⚠ same type
DOK6 p.Arg246Leu Uncertain significance ★ ⚠ same type
DOK6 p.Arg246Trp Uncertain significance ★ ⚠ 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/dok6-p-leu21phe (accessed [today's date]).

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