Is DOLK p.Ala504Ser (c.1510G>T) pathogenic?

DOLK p.Ala504Ser (c.1510G>T) is classified Uncertain significance in DOLK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely benign (0.0989); Ultra-rare (popmax 0.0154%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DOLK p.Ala504Ser (c.1510G>T)?

DOLK p.Ala504Ser (c.1510G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is DOLK p.Ala504Ser (c.1510G>T) in the general population?

DOLK p.Ala504Ser (c.1510G>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about DOLK p.Ala504Ser (c.1510G>T)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

DOLK p.Ala504Ser

c.1510G>T · VCV4014379

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -6.38	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 1.9	GERP -0.33, phastCons 0.94
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	6.397	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 0.0154% South Asian · 14/91,092 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.000929% 15/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,507
European (non-Finnish)	8.47e-05%	1,180,043

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.Ala504Ser
Coding: c.1510G>T
MANE Select: NM_014908
Type: single nucleotide variant
Location: chr9:128945794 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.37
Residue 504: 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.Ala504Thr Uncertain significance ★★ ⚠ same residue
DOLK p.Ala504= 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-ala504ser (accessed [today's date]).

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