Is DOLK p.Pro8Ala (c.22C>G) pathogenic?

DOLK p.Pro8Ala (c.22C>G) is classified Uncertain significance in DOLK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely benign (0.0475); Very rare (popmax 0.00439%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DOLK p.Pro8Ala (c.22C>G)?

DOLK p.Pro8Ala (c.22C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is DOLK p.Pro8Ala (c.22C>G) in the general population?

DOLK p.Pro8Ala (c.22C>G) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about DOLK p.Pro8Ala (c.22C>G)?

AlphaMissense predicts likely benign (score 0.0475) — an in-silico prediction, not a clinical call.

DOLK p.Pro8Ala

c.22C>G · VCV4244191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0475 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0475	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -3.8, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	8.983	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00439% South Asian · 4/91,048 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000372% 6/1,613,018 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,762
European (non-Finnish)	0.000169%	589,995

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.Pro8Ala
Coding: c.22C>G
MANE Select: NM_014908
Type: single nucleotide variant
Location: chr9:128947282 (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.Pro8Ser Uncertain significance ★★ ⚠ same residue
DOLK p.Pro8= Likely benign ★★ same residue
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

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-pro8ala (accessed [today's date]).

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