Is DLD p.Asp448fs (c.1344_1347del) pathogenic?

DLD p.Asp448fs (c.13441347del) is classified Pathogenic/Likely pathogenic in DLD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-18). Very rare (popmax 0.00223%, eas); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Asp448fs (c.1344_1347del)?

DLD p.Asp448fs (c.1344_1347del) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Asp448fs (c.1344_1347del) in the general population?

DLD p.Asp448fs (c.1344_1347del) is very rare (popmax 0.00223%, 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.Asp448fs

c.1344_1347del · rs1402761530 · VCV856335

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 12 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Overall
CADD	35.0	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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,613,880 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
South Asian	0.0011%	91,088
European (non-Finnish)	0.000678%	147,491

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.Asp448fs
Coding: c.1344_1347del
MANE Select: NM_000108
dbSNP: rs1402761530
Type: Microsatellite
Location: chr7:107918025 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 448: a functional site (important for interaction with pdhx and activity of multienzyme pyruvate dehydrogenase complex)

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.Asp448Gly Uncertain significance ★★ ⚠ same residue
DLD p.Asp448= Likely benign ★ same residue
DLD p.His96fs Pathogenic/Likely pathogenic ★★ same condition
DLD c.337+4_337+7del Likely pathogenic ★ same condition
DLD p.Arg482fs Pathogenic ★ same condition
DLD p.His396fs Likely pathogenic ★ same condition
DLD p.Leu76fs Likely pathogenic ★ same condition
DLD p.Tyr8fs 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-asp448fs (accessed [today's date]).

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