Is DLD p.Pro87Ser (c.259C>T) pathogenic?

DLD p.Pro87Ser (c.259C>T) is classified Likely pathogenic in DLD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.9946); Very rare (popmax 8.48e-05%, nfe); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Pro87Ser (c.259C>T)?

DLD p.Pro87Ser (c.259C>T) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Pro87Ser (c.259C>T) in the general population?

DLD p.Pro87Ser (c.259C>T) is very rare (popmax 8.48e-05%, 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.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

DLD p.Pro87Ser

c.259C>T · rs925493461 · VCV3241338

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic ✓ concordant with ClinVar · top 7% in DLD
REVEL	0.529	indeterminate
SaProt	LLR -13.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	28.1	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 8.48e-05% European (non-Finnish) · 1/1,179,786 alleles

Overall 6.2e-05% 1/1,613,742 alleles · very rare exomes 1/1,461,522 · genomes 0/152,220 · joint denominator

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.Pro87Ser
Coding: c.259C>T
MANE Select: NM_000108
dbSNP: rs925493461
Type: single nucleotide variant
Location: chr7:107902385 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 87: an α-helix

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-pro87ser (accessed [today's date]).

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