Is DLD p.Glu375Lys (c.1123G>A) pathogenic?

DLD p.Glu375Lys (c.1123G>A) is classified Pathogenic/Likely pathogenic in DLD (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.9156); Very rare (popmax 0.00136%, nfe); Associated with DLD-related disorder.

What condition is associated with DLD p.Glu375Lys (c.1123G>A)?

DLD p.Glu375Lys (c.1123G>A) is associated with DLD-related disorder, pyruvate dehydrogenase E3 deficiency (ClinVar).

How common is DLD p.Glu375Lys (c.1123G>A) in the general population?

DLD p.Glu375Lys (c.1123G>A) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about DLD p.Glu375Lys (c.1123G>A)?

AlphaMissense predicts likely pathogenic (score 0.9156) — an in-silico prediction, not a clinical call.

DLD p.Glu375Lys

c.1123G>A · rs121964992 · VCV11971

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.9156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DLD-related disorder

Computational evidence

Protein change
AlphaMissense	0.9156	likely pathogenic ✓ concordant with ClinVar
REVEL	0.643	indeterminate
SaProt	LLR -14.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	34.0	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 0.00136% European (non-Finnish) · 16/1,180,030 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0057% 92/1,614,052 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.223%	448
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.00136%	73,752
African / African-American	0.00133%	74,926

Ashkenazi Jewish 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.Glu375Lys
Coding: c.1123G>A
MANE Select: NM_000108
dbSNP: rs121964992
Type: single nucleotide variant
Location: chr7:107917349 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 375: an α-helix; a UniProt-annotated variant site (in dldd; loss of enzyme activity; abolished interaction with pdhx)

Full DLD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DLD-related disorder

Also linked: pyruvate dehydrogenase E3 deficiency

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-glu375lys (accessed [today's date]).

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