Is DOLK p.Arg211Cys (c.631C>T) pathogenic?

DOLK p.Arg211Cys (c.631C>T) is classified Conflicting classifications of pathogenicity in DOLK (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2013); Rare (popmax 0.406%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DOLK p.Arg211Cys (c.631C>T)?

DOLK p.Arg211Cys (c.631C>T) is associated with Cardiovascular phenotype, DK1-congenital disorder of glycosylation (ClinVar).

How common is DOLK p.Arg211Cys (c.631C>T) in the general population?

DOLK p.Arg211Cys (c.631C>T) is rare (popmax 0.406%, nfe) (gnomAD).

What do computational predictors say about DOLK p.Arg211Cys (c.631C>T)?

AlphaMissense predicts likely benign (score 0.2013) — an in-silico prediction, not a clinical call.

DOLK p.Arg211Cys

c.631C>T · rs145310298 · VCV95646

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.2013 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.406%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2013	likely benign
REVEL	0.591	indeterminate
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.78, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	24.6	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 0.406% European (non-Finnish) · 4,787/1,180,022 alleles

Filtering AF 0.396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.392%

Overall 0.332% 5,357/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.406%	247
Remaining individualsnot grpmax-eligible	0.362%	277
Admixed American	0.255%	392
Middle Eastern	0.181%	551
South Asian	0.0944%	1,059
African / African-American	0.076%	1,316
Finnishnot grpmax-eligible	0.0562%	1,779
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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: DOLK
Protein: p.Arg211Cys
Coding: c.631C>T
MANE Select: NM_014908
dbSNP: rs145310298
Type: single nucleotide variant
Location: chr9:128946673 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.37

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: DK1-congenital disorder of glycosylation

Similar variants

DOLK p.Arg211His Uncertain significance ★★ ⚠ same residue
DOLK p.Arg211= Conflicting classifications of pathogenicity ★ same residue
DOLK p.His408Asp Pathogenic/Likely pathogenic ★★ same condition
DOLK p.Met1Ile Pathogenic/Likely pathogenic ★★ same condition
DOLK p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
DOLK c.-194G>T Uncertain significance ★★ same condition
DOLK c.-22G>A Uncertain significance ★★ same condition
DOLK c.-269G>T 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/dolk-p-arg211cys (accessed [today's date]).

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