Is DLAT p.Val318Ala (c.953T>C) pathogenic?

DLAT p.Val318Ala (c.953T>C) is classified Benign in DLAT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.059); Common (popmax 78.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with pyruvate dehydrogenase E2 deficiency.

What condition is associated with DLAT p.Val318Ala (c.953T>C)?

DLAT p.Val318Ala (c.953T>C) is associated with pyruvate dehydrogenase E2 deficiency (ClinVar).

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.Val318Ala (c.953T>C)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

DLAT p.Val318Ala

Q: How common is DLAT p.Val318Ala (c.953T>C) in the general population?

DLAT p.Val318Ala (c.953T>C) is common (popmax 78.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.953T>C · rs627441 · VCV128899

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 78.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate dehydrogenase E2 deficiency

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -4.80	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 -0.13	GERP -3
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.014 · regional, not allelic
Overall
CADD	10.93	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 78.4% African / African-American · 58,801/74,994 alleles

Filtering AF 77.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 77.7%

Overall 40.5% 654,242/1,613,604 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	78.4%	1
East Asian	57%	2
Amishnot grpmax-eligible	54.7%	2
Admixed American	43.7%	2
Finnishnot grpmax-eligible	43.1%	2
Middle Eastern	42%	2
South Asian	41.7%	2
Remaining individualsnot grpmax-eligible	41.2%	2
European (non-Finnish)	37.3%	3
Ashkenazi Jewishnot grpmax-eligible	30%	3

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.Val318Ala
Coding: c.953T>C
MANE Select: NM_001931
dbSNP: rs627441
Type: single nucleotide variant
Location: chr11:112037438 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 13 PDB
Residue 318: a UniProt-annotated variant site (in); 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-val318ala (accessed [today's date]).

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