Is DLD p.Arg19Gly (c.55C>G) pathogenic?

DLD p.Arg19Gly (c.55C>G) is classified Conflicting classifications of pathogenicity in DLD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0913); Ultra-rare (popmax 0.0579%, nfe); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Arg19Gly (c.55C>G)?

DLD p.Arg19Gly (c.55C>G) is associated with pyruvate dehydrogenase E3 deficiency, Leigh syndrome, pyruvate dehydrogenase deficiency (ClinVar).

How common is DLD p.Arg19Gly (c.55C>G) in the general population?

DLD p.Arg19Gly (c.55C>G) is ultra-rare (popmax 0.0579%, 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.Arg19Gly (c.55C>G)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

DLD p.Arg19Gly

c.55C>G · rs144038427 · VCV578582

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0579%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP 1.1, phastCons 0.53
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	19.14	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 0.0579% European (non-Finnish) · 683/1,179,588 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.0459% 741/1,613,344 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0579%	1,727
Admixed American	0.0434%	2,305
Remaining individualsnot grpmax-eligible	0.0272%	3,675
African / African-American	0.012%	8,335
Finnishnot grpmax-eligible	0.00938%	10,665

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.Arg19Gly
Coding: c.55C>G
MANE Select: NM_000108
dbSNP: rs144038427
Type: single nucleotide variant
Location: chr7:107893215 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB

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

Also linked: Leigh syndrome pyruvate dehydrogenase deficiency

For Maple syrup urine disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

DLD p.Arg19= Likely benign ★ 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
DLD c.875+1G>A Pathogenic/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-arg19gly (accessed [today's date]).

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