Is DLD p.Pro488= (c.1464G>A) pathogenic?

DLD p.Pro488= (c.1464G>A) is classified Uncertain significance in DLD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-23). Very rare (popmax 0.00133%, afr); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Pro488= (c.1464G>A)?

DLD p.Pro488= (c.1464G>A) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Pro488= (c.1464G>A) in the general population?

DLD p.Pro488= (c.1464G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Maple syrup urine disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DLD p.Pro488=

c.1464G>A · rs760788506 · VCV1932265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.91	donor loss · deltas
Pangolin	Δ0.77	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 0.23, phastCons 1
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,992 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00062% 10/1,613,296 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,995
African / African-Americangrpmax	0.00133%	74,992
South Asian	0.0011%	91,066
European (non-Finnish)	0.000509%	196,561

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro488=
Coding: c.1464G>A
MANE Select: NM_000108
dbSNP: rs760788506
Type: single nucleotide variant
Location: chr7:107919099 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 488: a UniProt-annotated variant site (in dldd; no effect on interaction with pdhx)

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.Pro488Leu Likely pathogenic ★★ same residue
DLD p.Pro488fs Likely pathogenic ★ 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-pro488 (accessed [today's date]).

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