Is DLAT p.Ser227= (c.681T>C) pathogenic?

DLAT p.Ser227= (c.681T>C) is classified Likely benign in DLAT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-20). Very rare (popmax 0.00407%, nfe); Associated with pyruvate dehydrogenase E2 deficiency.

What condition is associated with DLAT p.Ser227= (c.681T>C)?

DLAT p.Ser227= (c.681T>C) is associated with pyruvate dehydrogenase E2 deficiency (ClinVar).

How common is DLAT p.Ser227= (c.681T>C) in the general population?

DLAT p.Ser227= (c.681T>C) is very rare (popmax 0.00407%, nfe) (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.Ser227=

c.681T>C · rs781985635 · VCV1650702

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

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 0.31	GERP -2.2, phastCons 1
Overall
CADD	9.244	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00407% European (non-Finnish) · 48/1,179,836 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00328% 53/1,613,618 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,619
European (non-Finnish)grpmax	0.00407%	24,580
African / African-American	0.00134%	74,876

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: DLAT
Protein: p.Ser227=
Coding: c.681T>C
MANE Select: NM_001931
dbSNP: rs781985635
Type: single nucleotide variant
Location: chr11:112033424 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 13 PDB
Residue 227: the lipoyl-binding 2 domain

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-ser227 (accessed [today's date]).

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