Is DLAT p.Pro195Ser (c.583C>T) pathogenic?

DLAT p.Pro195Ser (c.583C>T) is classified Conflicting classifications of pathogenicity in DLAT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.0712); Very rare (popmax 0.01%, amr); Associated with pyruvate dehydrogenase E2 deficiency.

What condition is associated with DLAT p.Pro195Ser (c.583C>T)?

DLAT p.Pro195Ser (c.583C>T) is associated with pyruvate dehydrogenase E2 deficiency (ClinVar).

How common is DLAT p.Pro195Ser (c.583C>T) in the general population?

DLAT p.Pro195Ser (c.583C>T) is very rare (popmax 0.01%, amr) (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 DLAT p.Pro195Ser (c.583C>T)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

DLAT p.Pro195Ser

c.583C>T · rs149440666 · VCV214293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate dehydrogenase E2 deficiency

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -8.15	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 0.68	GERP -0.78, phastCons 0.1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.014 · regional, not allelic
Overall
CADD	15.5	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 0.01% Admixed American · 6/60,006 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00353% 57/1,614,098 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
European (non-Finnish)	0.00407%	24,584
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,932
South Asian	0.0011%	91,094

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.Pro195Ser
Coding: c.583C>T
MANE Select: NM_001931
dbSNP: rs149440666
Type: single nucleotide variant
Location: chr11:112028868 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 13 PDB
Residue 195: 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-pro195ser (accessed [today's date]).

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