Is DOLK p.Ala336Pro (c.1006G>C) pathogenic?

DOLK p.Ala336Pro (c.1006G>C) is classified Uncertain significance in DOLK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-22). AlphaMissense: ambiguous (0.3605); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with DOLK p.Ala336Pro (c.1006G>C)?

DOLK p.Ala336Pro (c.1006G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is DOLK p.Ala336Pro (c.1006G>C) in the general population?

DOLK p.Ala336Pro (c.1006G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DOLK p.Ala336Pro (c.1006G>C)?

AlphaMissense predicts ambiguous (score 0.3605) — an in-silico prediction, not a clinical call.

DOLK p.Ala336Pro

c.1006G>C · rs769241947 · VCV3226322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3605 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3605	ambiguous
REVEL	0.362	indeterminate
SaProt	LLR -6.20	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.96	GERP -3.3
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	12.41	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DOLK
Protein: p.Ala336Pro
Coding: c.1006G>C
MANE Select: NM_014908
dbSNP: rs769241947
Type: single nucleotide variant
Location: chr9:128946298 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.37
Residue 336: a UniProt-annotated variant site (in cdg1m)

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.Ala336= Likely benign ★ same residue
DOLK p.Ala336Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ala336pro (accessed [today's date]).

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