Is DOLK p.Gln331His (c.993G>C) pathogenic?

DOLK p.Gln331His (c.993G>C) is classified Uncertain significance in DOLK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-24). AlphaMissense: likely benign (0.1586); Very rare (popmax 0.000169%, nfe); Associated with DK1-congenital disorder of glycosylation.

What condition is associated with DOLK p.Gln331His (c.993G>C)?

DOLK p.Gln331His (c.993G>C) is associated with DK1-congenital disorder of glycosylation (ClinVar).

How common is DOLK p.Gln331His (c.993G>C) in the general population?

DOLK p.Gln331His (c.993G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is DK1-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DOLK p.Gln331His (c.993G>C)?

AlphaMissense predicts likely benign (score 0.1586) — an in-silico prediction, not a clinical call.

DOLK p.Gln331His

c.993G>C · rs1841665962 · VCV1346236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DK1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1586	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.50	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 0.43	GERP 0.61, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 1,613 bp · p 0.00089 · regional, not allelic
Overall
CADD	16.18	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 0.000169% European (non-Finnish) · 2/1,180,032 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,890 alleles · very rare

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.Gln331His
Coding: c.993G>C
MANE Select: NM_014908
dbSNP: rs1841665962
Type: single nucleotide variant
Location: chr9:128946311 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.37
Residue 331: a UniProt-annotated variant site (in cdg1m)

Full DOLK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DK1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For DK1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DOLK p.Gln331Arg Uncertain significance ★ ⚠ same residue
DOLK p.Gln331Ter Likely pathogenic ★ same residue
DOLK p.Gln331Lys Uncertain significance ★ ⚠ 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

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-gln331his (accessed [today's date]).

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