Is DLD p.Met123Val (c.367A>G) pathogenic?

DLD p.Met123Val (c.367A>G) is classified Uncertain significance in DLD (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-21). AlphaMissense: ambiguous (0.3851); Very rare (popmax 8.48e-05%, nfe); Associated with pyruvate dehydrogenase E3 deficiency.

What condition is associated with DLD p.Met123Val (c.367A>G)?

DLD p.Met123Val (c.367A>G) is associated with pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Met123Val (c.367A>G) in the general population?

DLD p.Met123Val (c.367A>G) 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.Met123Val (c.367A>G)?

AlphaMissense predicts ambiguous (score 0.3851) — an in-silico prediction, not a clinical call.

DLD p.Met123Val

c.367A>G · rs111352707 · VCV649784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3851 · ACMG-weighted

gnomAD v4.1

Rare

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

Conditions

pyruvate dehydrogenase E3 deficiency

Computational evidence

Protein change
AlphaMissense	0.3851	ambiguous
REVEL	0.379	indeterminate
SaProt	LLR -10.29	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	24.9	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) · 1/1,179,484 alleles

Overall 0.000205% 3/1,460,924 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,232
European (non-Finnish)grpmax	8.48e-05%	1,179,485

Remaining individuals 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.Met123Val
Coding: c.367A>G
MANE Select: NM_000108
dbSNP: rs111352707
Type: single nucleotide variant
Location: chr7:107904987 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 123: 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-met123val (accessed [today's date]).

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