Is DOK7 p.Arg159Cys (c.475C>T) pathogenic?

DOK7 p.Arg159Cys (c.475C>T) is classified Uncertain significance in DOK7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-08-28). AlphaMissense: likely pathogenic (0.6185); Very rare (popmax 0.00659%, sas).

How common is DOK7 p.Arg159Cys (c.475C>T) in the general population?

DOK7 p.Arg159Cys (c.475C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about DOK7 p.Arg159Cys (c.475C>T)?

AlphaMissense predicts likely pathogenic (score 0.6185) — an in-silico prediction, not a clinical call.

DOK7 p.Arg159Cys

c.475C>T · rs368891521 · VCV1305070

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6185	likely pathogenic
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.3, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,066 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00285% 46/1,613,882 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
Remaining individualsnot grpmax-eligible	0.0048%	20,837
African / African-American	0.004%	25,014
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)	0.00271%	36,876
Finnishnot grpmax-eligible	0.00157%	63,750

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: DOK7
Protein: p.Arg159Cys
Coding: c.475C>T
MANE Select: NM_173660
dbSNP: rs368891521
Type: single nucleotide variant
Location: chr4:3476485 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 159: the irs-type ptb domain

Full DOK7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOK7 p.Arg159His Uncertain significance ★ ⚠ same residue
DOK7 c.331+1G>T Pathogenic ★★ same type
DOK7 c.332-1G>A Likely pathogenic ★★ same type
DOK7 c.332-1G>C Likely pathogenic ★★ same type
DOK7 c.332-1G>T Likely pathogenic ★★ same type
DOK7 p.Arg158Gln Pathogenic/Likely pathogenic ★★ same type
DOK7 p.Arg201Ter Pathogenic ★★ same type
DOK7 p.Cys412Ter 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/dok7-p-arg159cys (accessed [today's date]).

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