Is DLD p.Leu274fs (c.821dup) pathogenic?

DLD p.Leu274fs (c.821dup) is classified Pathogenic/Likely pathogenic in DLD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-05). Very rare (popmax 0.00017%, nfe); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Leu274fs (c.821dup)?

DLD p.Leu274fs (c.821dup) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Leu274fs (c.821dup) in the general population?

DLD p.Leu274fs (c.821dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Maple syrup urine disease inherited?

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

DLD p.Leu274fs

c.821dup · rs751883130 · VCV960146

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP -2.9, phastCons 1
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,878 alleles

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

Overall 0.000248% 4/1,613,758 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,797
European (non-Finnish)grpmax	0.00017%	589,939

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu274fs
Coding: c.821dup
MANE Select: NM_000108
dbSNP: rs751883130
Type: Duplication
Location: chr7:107915640 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB

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

For Maple syrup urine disease (Orphanet):

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

Similar variants

DLD p.Ser28fs Pathogenic/Likely pathogenic ★★ same condition
DLD p.Ala363fs Likely pathogenic ★ same condition
DLD p.Ala381fs Likely pathogenic ★ same condition
DLD p.Glu330Ter Pathogenic ★ same condition
DLD p.Glu412fs Likely pathogenic ★ same condition
DLD p.Ile371fs Likely pathogenic ★ same condition
DLD p.Thr199fs Likely pathogenic ★ same condition
DLD p.Val7fs 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-leu274fs (accessed [today's date]).

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