Is DLAT p.Pro323= (c.969A>C) pathogenic?

DLAT p.Pro323= (c.969A>C) is classified Likely benign in DLAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0434%, amr); Associated with pyruvate dehydrogenase E2 deficiency.

What condition is associated with DLAT p.Pro323= (c.969A>C)?

DLAT p.Pro323= (c.969A>C) is associated with pyruvate dehydrogenase E2 deficiency (ClinVar).

How common is DLAT p.Pro323= (c.969A>C) in the general population?

DLAT p.Pro323= (c.969A>C) is ultra-rare (popmax 0.0434%, amr) (gnomAD).

How is Pyruvate dehydrogenase deficiency inherited?

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

DLAT p.Pro323=

c.969A>C · rs587627931 · VCV746386

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0434%, amr)

Conditions

pyruvate dehydrogenase E2 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -3.8
Overall
CADD	1.644	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0434% Admixed American · 26/59,946 alleles

Filtering AF 0.0304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00527% 85/1,613,368 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0434%	2,306
Remaining individualsnot grpmax-eligible	0.0256%	3,905
European (non-Finnish)	0.00356%	28,086
African / African-American	0.00134%	74,886

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: DLAT
Protein: p.Pro323=
Coding: c.969A>C
MANE Select: NM_001931
dbSNP: rs587627931
Type: single nucleotide variant
Location: chr11:112037454 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 13 PDB
Residue 323: the 'disordered' region

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

Disease context

pyruvate dehydrogenase E2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pyruvate dehydrogenase deficiency (Orphanet):

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

Similar variants

DLAT c.976-1G>A Pathogenic/Likely pathogenic ★★ same condition
DLAT p.Arg435Ter Pathogenic ★★ same condition
DLAT p.Glu138Ter Pathogenic ★★ same condition
DLAT p.Val157Gly Likely pathogenic ★★ same condition
DLAT c.1130-6T>G Uncertain significance ★★ same condition
DLAT p.Ala109Thr Uncertain significance ★★ ⚠ same condition
DLAT p.Ala191Gly Uncertain significance ★★ ⚠ same condition
DLAT p.Ala191Val Uncertain significance ★★ ⚠ 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/dlat-p-pro323 (accessed [today's date]).

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