Is DLAT p.Arg461Gln (c.1382G>A) pathogenic?

DLAT p.Arg461Gln (c.1382G>A) is classified Conflicting classifications of pathogenicity in DLAT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.7017); Ultra-rare (popmax 0.021%, sas); Associated with pyruvate dehydrogenase E2 deficiency.

What condition is associated with DLAT p.Arg461Gln (c.1382G>A)?

DLAT p.Arg461Gln (c.1382G>A) is associated with pyruvate dehydrogenase E2 deficiency (ClinVar).

How common is DLAT p.Arg461Gln (c.1382G>A) in the general population?

DLAT p.Arg461Gln (c.1382G>A) is ultra-rare (popmax 0.021%, sas) (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.Arg461Gln (c.1382G>A)?

AlphaMissense predicts likely pathogenic (score 0.7017) — an in-silico prediction, not a clinical call.

DLAT p.Arg461Gln

c.1382G>A · rs782807951 · VCV1312384

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7017 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pyruvate dehydrogenase E2 deficiency

Computational evidence

Protein change
AlphaMissense	0.7017	likely pathogenic
REVEL	0.443	indeterminate
SaProt	LLR -12.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.014 · regional, not allelic
Overall
CADD	28.4	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 0.021% South Asian · 19/90,604 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00363% 58/1,596,908 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.021%	4,769
Middle Eastern	0.0167%	5,982
Remaining individualsnot grpmax-eligible	0.00646%	15,486
Finnishnot grpmax-eligible	0.00313%	31,932
European (non-Finnish)	0.00266%	37,571
Admixed American	0.00167%	59,988

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.Arg461Gln
Coding: c.1382G>A
MANE Select: NM_001931
dbSNP: rs782807951
Type: single nucleotide variant
Location: chr11:112045954 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 13 PDB
Residue 461: a binding site; an α-helix

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 p.Arg461Trp Uncertain significance ★ ⚠ same residue
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

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-arg461gln (accessed [today's date]).

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