Is DLD p.Ile47Thr (c.140T>C) pathogenic?

DLD p.Ile47Thr (c.140T>C) is classified Conflicting classifications of pathogenicity in DLD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.8381); Very rare (popmax 0.00017%, nfe); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Ile47Thr (c.140T>C)?

DLD p.Ile47Thr (c.140T>C) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Ile47Thr (c.140T>C) in the general population?

DLD p.Ile47Thr (c.140T>C) 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.

What do computational predictors say about DLD p.Ile47Thr (c.140T>C)?

AlphaMissense predicts likely pathogenic (score 0.8381) — an in-silico prediction, not a clinical call.

DLD p.Ile47Thr

c.140T>C · rs397514651 · VCV40188

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
AlphaMissense	0.8381	likely pathogenic
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -16.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	29.9	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 0.00017% European (non-Finnish) · 2/1,179,646 alleles

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

Overall 0.000137% 2/1,461,368 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.Ile47Thr
Coding: c.140T>C
MANE Select: NM_000108
dbSNP: rs397514651
Type: single nucleotide variant
Location: chr7:107901759 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 47: a UniProt-annotated variant site (in dldd); a β-strand

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.Ile47Arg Uncertain significance ★ ⚠ 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
DLD c.875+1G>A 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/dld-p-ile47thr (accessed [today's date]).

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