Is DOLK p.Val127Ala (c.380T>C) pathogenic?

DOLK p.Val127Ala (c.380T>C) is classified Conflicting classifications of pathogenicity in DOLK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.2497); Rare (popmax 0.129%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DOLK p.Val127Ala (c.380T>C)?

DOLK p.Val127Ala (c.380T>C) is associated with Cardiovascular phenotype, DK1-congenital disorder of glycosylation (ClinVar).

How common is DOLK p.Val127Ala (c.380T>C) in the general population?

DOLK p.Val127Ala (c.380T>C) is rare (popmax 0.129%, eas) (gnomAD).

What do computational predictors say about DOLK p.Val127Ala (c.380T>C)?

AlphaMissense predicts likely benign (score 0.2497) — an in-silico prediction, not a clinical call.

DOLK p.Val127Ala

c.380T>C · rs201629680 · VCV1094058

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2497 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.129%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2497	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -5.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	23.7	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 0.129% East Asian · 58/44,860 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0931%

Overall 0.00393% 63/1,603,890 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.129%	773
Remaining individualsnot grpmax-eligible	0.0016%	62,426
European (non-Finnish)	0.000339%	294,938

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.Val127Ala
Coding: c.380T>C
MANE Select: NM_014908
dbSNP: rs201629680
Type: single nucleotide variant
Location: chr9:128946924 (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

Also linked: DK1-congenital disorder of glycosylation

Similar variants

DOLK p.Val127Met Uncertain significance ★★ ⚠ same residue
DOLK p.Val127= Likely benign ★ same residue
DOLK p.His408Asp Pathogenic/Likely pathogenic ★★ same condition
DOLK p.Met1Ile Pathogenic/Likely pathogenic ★★ same condition
DOLK p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
DOLK c.-194G>T Uncertain significance ★★ same condition
DOLK c.-22G>A Uncertain significance ★★ same condition
DOLK c.-269G>T 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-val127ala (accessed [today's date]).

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