Is DOLK p.Ile464Ser (c.1391T>G) pathogenic?

DOLK p.Ile464Ser (c.1391T>G) is classified Uncertain significance in DOLK (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-02). AlphaMissense: likely pathogenic (0.626); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with DOLK p.Ile464Ser (c.1391T>G)?

DOLK p.Ile464Ser (c.1391T>G) is associated with Cardiovascular phenotype (ClinVar).

How common is DOLK p.Ile464Ser (c.1391T>G) in the general population?

DOLK p.Ile464Ser (c.1391T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DOLK p.Ile464Ser (c.1391T>G)?

AlphaMissense predicts likely pathogenic (score 0.626) — an in-silico prediction, not a clinical call.

DOLK p.Ile464Ser

c.1391T>G · rs2492002844 · VCV1771565

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.626 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.626	likely pathogenic
REVEL	0.302	indeterminate
SaProt	LLR -7.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	24.0	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.Ile464Ser
Coding: c.1391T>G
MANE Select: NM_014908
dbSNP: rs2492002844
Type: single nucleotide variant
Location: chr9:128945913 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.37
Residue 464: the 'ctp-binding' region; 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.Ile464= 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
DOLK p.Ala504Thr 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-ile464ser (accessed [today's date]).

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