Is DLD p.Glu125= (c.375G>A) pathogenic?

DLD p.Glu125= (c.375G>A) is classified Conflicting classifications of pathogenicity in DLD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-05). Ultra-rare (popmax 0.0246%, eas); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Glu125= (c.375G>A)?

DLD p.Glu125= (c.375G>A) is associated with pyruvate dehydrogenase E3 deficiency, Leigh syndrome, pyruvate dehydrogenase deficiency (ClinVar).

How common is DLD p.Glu125= (c.375G>A) in the general population?

DLD p.Glu125= (c.375G>A) is ultra-rare (popmax 0.0246%, eas) (gnomAD).

How is Maple syrup urine disease inherited?

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

DLD p.Glu125=

c.375G>A · rs559057715 · VCV751771

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, eas)

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.36	GERP 0.23, phastCons 0.97
Overall
CADD	6.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0246% East Asian · 11/44,800 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000868% 14/1,613,218 alleles · ultra-rare exomes 9/1,460,974 · genomes 5/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0246%	4,073
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	0.00017%	589,765

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: DLD
Protein: p.Glu125=
Coding: c.375G>A
MANE Select: NM_000108
dbSNP: rs559057715
Type: single nucleotide variant
Location: chr7:107904995 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 125: an α-helix

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

Disease context

pyruvate dehydrogenase E3 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leigh syndrome pyruvate dehydrogenase deficiency

For Maple syrup urine disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

DLD c.1464+1G>A Pathogenic/Likely pathogenic ★★ same condition
DLD c.198+1G>T Likely pathogenic ★★ same condition
DLD c.39+1G>A Likely pathogenic ★★ same condition
DLD c.40-2A>G Likely pathogenic ★★ same condition
DLD c.583-1G>C Likely pathogenic ★★ same condition
DLD c.684+1G>T Likely pathogenic ★★ same condition
DLD c.875+1G>A Pathogenic/Likely pathogenic ★★ same condition
DLD p.Arg315Ter 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/dld-p-glu125 (accessed [today's date]).

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