Is DLD p.Asp448Gly (c.1343A>G) pathogenic?

DLD p.Asp448Gly (c.1343A>G) is classified Uncertain significance in DLD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-05). AlphaMissense: ambiguous (0.5317); Very rare (popmax 0.0011%, sas); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Asp448Gly (c.1343A>G)?

DLD p.Asp448Gly (c.1343A>G) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Asp448Gly (c.1343A>G) in the general population?

DLD p.Asp448Gly (c.1343A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Maple syrup urine disease inherited?

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

What do computational predictors say about DLD p.Asp448Gly (c.1343A>G)?

AlphaMissense predicts ambiguous (score 0.5317) — an in-silico prediction, not a clinical call.

DLD p.Asp448Gly

c.1343A>G · rs778579492 · VCV2440800

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
AlphaMissense	0.5317	ambiguous
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -9.99	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	29.4	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 0.0011% South Asian · 1/91,086 alleles

Overall 6.84e-05% 1/1,461,720 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: DLD
Protein: p.Asp448Gly
Coding: c.1343A>G
MANE Select: NM_000108
dbSNP: rs778579492
Type: single nucleotide variant
Location: chr7:107918030 (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.Asp448= Likely benign ★ same residue
DLD p.Asp448fs Pathogenic/Likely pathogenic ★★ same residue
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

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-asp448gly (accessed [today's date]).

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