Is DLD p.Ala12Thr (c.34G>A) pathogenic?

DLD p.Ala12Thr (c.34G>A) is classified Benign/Likely benign in DLD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1294); Low-frequency (popmax 2.08%, afr); Associated with pyruvate dehydrogenase deficiency.

What condition is associated with DLD p.Ala12Thr (c.34G>A)?

DLD p.Ala12Thr (c.34G>A) is associated with pyruvate dehydrogenase deficiency, pyruvate dehydrogenase E3 deficiency, Leigh syndrome (ClinVar).

How common is DLD p.Ala12Thr (c.34G>A) in the general population?

DLD p.Ala12Thr (c.34G>A) is low-frequency (popmax 2.08%, afr) (gnomAD).

How is Pyruvate dehydrogenase deficiency inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DLD p.Ala12Thr (c.34G>A)?

AlphaMissense predicts likely benign (score 0.1294) — an in-silico prediction, not a clinical call.

DLD p.Ala12Thr

c.34G>A · rs75077312 · VCV137103

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1294 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.08%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.1294	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -7.33	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 8.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	22.8	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 2.08% African / African-American · 1,559/75,058 alleles

Filtering AF 1.99% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.96%

Overall 0.109% 1,759/1,614,124 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.08%	48
Admixed American	0.16%	625
Remaining individualsnot grpmax-eligible	0.112%	893
Middle Eastern	0.066%	1,515
South Asian	0.00769%	13,012
European (non-Finnish)	0.00195%	51,303

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.Ala12Thr
Coding: c.34G>A
MANE Select: NM_000108
dbSNP: rs75077312
Type: single nucleotide variant
Location: chr7:107891284 (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 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate dehydrogenase E3 deficiency Leigh syndrome

For Pyruvate dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive, Not applicable, X-linked dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

DLD p.Ala12= 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-ala12thr (accessed [today's date]).

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