Is DOLK p.Glu23Ala (c.68A>C) pathogenic?

DOLK p.Glu23Ala (c.68A>C) is classified Uncertain significance in DOLK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-12). AlphaMissense: likely pathogenic (0.7753); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DOLK p.Glu23Ala (c.68A>C)?

DOLK p.Glu23Ala (c.68A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is DOLK p.Glu23Ala (c.68A>C) in the general population?

DOLK p.Glu23Ala (c.68A>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DOLK p.Glu23Ala (c.68A>C)?

AlphaMissense predicts likely pathogenic (score 0.7753) — an in-silico prediction, not a clinical call.

DOLK p.Glu23Ala

c.68A>C · VCV4056044

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7753	likely pathogenic
REVEL	0.771	pathogenic-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	25.7	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 0.00133% African / African-American · 1/75,012 alleles

Overall 6.84e-05% 1/1,461,276 alleles · very rare

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.Glu23Ala
Coding: c.68A>C
MANE Select: NM_014908
Type: single nucleotide variant
Location: chr9:128947236 (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

Similar variants

DOLK p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
DOLK p.Ala194Val Uncertain significance ★★ ⚠ same condition
DOLK p.Ala25Thr Uncertain significance ★★ ⚠ same condition
DOLK p.Ala363Thr Uncertain significance ★★ ⚠ same condition
DOLK p.Ala435Pro Uncertain significance ★★ ⚠ same condition
DOLK p.Ala482Val Uncertain significance ★★ ⚠ same condition
DOLK p.Ala504Thr Uncertain significance ★★ ⚠ same condition
DOLK p.Arg109Ser 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-glu23ala (accessed [today's date]).

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