Is DLD p.Leu451= (c.1351C>T) pathogenic?

DLD p.Leu451= (c.1351C>T) is classified Benign in DLD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 14.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with pyruvate dehydrogenase deficiency.

What condition is associated with DLD p.Leu451= (c.1351C>T)?

DLD p.Leu451= (c.1351C>T) is associated with pyruvate dehydrogenase deficiency, pyruvate dehydrogenase E3 deficiency, Leigh syndrome (ClinVar).

How is Pyruvate dehydrogenase deficiency inherited?

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

DLD p.Leu451=

Q: How common is DLD p.Leu451= (c.1351C>T) in the general population?

DLD p.Leu451= (c.1351C>T) is common (popmax 14.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1351C>T · rs1803921 · VCV137100

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 14.6%, afr) — too common for a highly-penetrant pathogenic allele

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 -0.17	GERP -1.1
Overall
CADD	6.314	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.6% African / African-American · 10,971/74,976 alleles

Filtering AF 14.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.3%

Overall 0.766% 12,364/1,613,944 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	14.6%	7
Remaining individualsnot grpmax-eligible	0.974%	103
Admixed American	0.811%	123
Middle Eastern	0.808%	124
South Asian	0.0285%	3,503
European (non-Finnish)	0.0188%	5,315

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.Leu451=
Coding: c.1351C>T
MANE Select: NM_000108
dbSNP: rs1803921
Type: single nucleotide variant
Location: chr7:107918038 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 451: 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 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-leu451 (accessed [today's date]).

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