Is DLD p.Ile304Thr (c.911T>C) pathogenic?

DLD p.Ile304Thr (c.911T>C) is classified Conflicting classifications of pathogenicity in DLD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-27). AlphaMissense: ambiguous (0.5156); Rare (popmax 0.154%, afr); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Ile304Thr (c.911T>C)?

DLD p.Ile304Thr (c.911T>C) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Ile304Thr (c.911T>C) in the general population?

DLD p.Ile304Thr (c.911T>C) is rare (popmax 0.154%, afr) (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.Ile304Thr (c.911T>C)?

AlphaMissense predicts ambiguous (score 0.5156) — an in-silico prediction, not a clinical call.

DLD p.Ile304Thr

c.911T>C · rs150944645 · VCV2044628

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5156 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, afr)

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
AlphaMissense	0.5156	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -9.90	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	27.1	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 0.154% African / African-American · 115/74,738 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.00806% 130/1,613,368 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.154%	650
Admixed American	0.0167%	5,983
Remaining individualsnot grpmax-eligible	0.0064%	15,624
Finnishnot grpmax-eligible	0.00156%	63,910

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.Ile304Thr
Coding: c.911T>C
MANE Select: NM_000108
dbSNP: rs150944645
Type: single nucleotide variant
Location: chr7:107916829 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 304: 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 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-ile304thr (accessed [today's date]).

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