Is DGUOK p.Ala2Ser (c.4G>T) pathogenic?

DGUOK p.Ala2Ser (c.4G>T) is classified Conflicting classifications of pathogenicity in DGUOK (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1063); Rare (popmax 0.606%, nfe); Associated with mitochondrial DNA depletion syndrome 3 (hepatocerebral type).

What condition is associated with DGUOK p.Ala2Ser (c.4G>T)?

DGUOK p.Ala2Ser (c.4G>T) is associated with mitochondrial DNA depletion syndrome 3 (hepatocerebral type) (ClinVar).

How common is DGUOK p.Ala2Ser (c.4G>T) in the general population?

DGUOK p.Ala2Ser (c.4G>T) is rare (popmax 0.606%, nfe) (gnomAD).

What do computational predictors say about DGUOK p.Ala2Ser (c.4G>T)?

AlphaMissense predicts likely benign (score 0.1063) — an in-silico prediction, not a clinical call.

DGUOK p.Ala2Ser

Q: How is Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency inherited?

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

c.4G>T · rs147551003 · VCV193482

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1063 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.606%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Computational evidence

Protein change
AlphaMissense	0.1063	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -8.52	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 0.27	GERP -1.6, phastCons 0.005
Regional constraint	o/e 1.07	unconstrained · MANE · 32 kb · p 0.18 · regional, not allelic
Overall
CADD	11.74	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 0.606% European (non-Finnish) · 7,153/1,180,010 alleles

Filtering AF 0.594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.59%

Overall 0.482% 7,778/1,613,382 alleles · rare exomes 7,327/1,461,032 · genomes 451/152,350 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.606%	165
Remaining individualsnot grpmax-eligible	0.509%	197
Admixed American	0.253%	395
Amishnot grpmax-eligible	0.219%	456
African / African-American	0.101%	988
Ashkenazi Jewishnot grpmax-eligible	0.0743%	1,346
South Asian	0.0516%	1,938
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.00949%	10,535
East Asian	0.00223%	44,892

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: DGUOK
Protein: p.Ala2Ser
Coding: c.4G>T
MANE Select: NM_080916
dbSNP: rs147551003
Type: single nucleotide variant
Location: chr2:73926914 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.27 · 1 PDB

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

Disease context

mitochondrial DNA depletion syndrome 3 (hepatocerebral type) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

DGUOK p.Ala2= Likely benign ★ same residue
DGUOK c.444-62C>A Pathogenic/Likely pathogenic ★★ same condition
DGUOK p.Arg118His Pathogenic/Likely pathogenic ★★ same condition
DGUOK p.Arg142Lys Pathogenic/Likely pathogenic ★★ same condition
DGUOK p.Asp255Tyr Pathogenic/Likely pathogenic ★★ ⚠ same condition
DGUOK p.Gln197= Pathogenic/Likely pathogenic ★★ same condition
DGUOK p.Gln79Ter Pathogenic ★★ same condition
DGUOK p.Glu165Lys Pathogenic/Likely pathogenic ★★ 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/dguok-p-ala2ser (accessed [today's date]).

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