Is DLD p.Ile181= (c.543A>T) pathogenic?

DLD p.Ile181= (c.543A>T) is classified Conflicting classifications of pathogenicity in DLD (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-06-01). Rare (popmax 0.628%, amr); Associated with pyruvate dehydrogenase deficiency.

What condition is associated with DLD p.Ile181= (c.543A>T)?

DLD p.Ile181= (c.543A>T) is associated with pyruvate dehydrogenase deficiency, pyruvate dehydrogenase E3 deficiency, Leigh syndrome (ClinVar).

How common is DLD p.Ile181= (c.543A>T) in the general population?

DLD p.Ile181= (c.543A>T) is rare (popmax 0.628%, amr) (gnomAD).

How is Pyruvate dehydrogenase deficiency inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

DLD p.Ile181=

c.543A>T · rs61749952 · VCV137095

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.628%, amr)

Conditions

pyruvate dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.6, phastCons 1
Overall
CADD	6.676	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.628% Admixed American · 377/60,018 alleles

Filtering AF 0.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.585%

Overall 0.497% 8,021/1,613,824 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.628%	159
European (non-Finnish)	0.602%	166
Remaining individualsnot grpmax-eligible	0.467%	214
Ashkenazi Jewishnot grpmax-eligible	0.385%	260
African / African-American	0.137%	729
Middle Eastern	0.116%	866
Finnishnot grpmax-eligible	0.0453%	2,208
South Asian	0.0022%	45,540

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.Ile181=
Coding: c.543A>T
MANE Select: NM_000108
dbSNP: rs61749952
Type: single nucleotide variant
Location: chr7:107905465 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 181: a β-strand

Full DLD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pyruvate dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate dehydrogenase E3 deficiency Leigh syndrome

For Pyruvate dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive, Not applicable, X-linked dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

DLD p.Ile181Thr Uncertain significance ★ ⚠ same residue
DLD p.Ile181Val 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

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-ile181 (accessed [today's date]).

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