Is PDHX p.Val286= (c.858T>C) pathogenic?

PDHX p.Val286= (c.858T>C) is classified Benign in PDHX (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 72.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with pyruvate dehydrogenase E3-binding protein deficiency.

What condition is associated with PDHX p.Val286= (c.858T>C)?

PDHX p.Val286= (c.858T>C) is associated with pyruvate dehydrogenase E3-binding protein deficiency (ClinVar).

How is Pyruvate dehydrogenase deficiency inherited?

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

PDHX p.Val286=

Q: How common is PDHX p.Val286= (c.858T>C) in the general population?

PDHX p.Val286= (c.858T>C) is common (popmax 72.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.858T>C · rs497582 · VCV304473

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 72.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

pyruvate dehydrogenase E3-binding protein 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 0.065	GERP -3.8, phastCons 0.97
Overall
CADD	6.761	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 72.9% East Asian · 32,706/44,842 alleles

Filtering AF 72.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 72%

Overall 68% 1,095,704/1,611,864 alleles · common exomes 1,004,439/1,459,848 · genomes 91,265/152,016 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	81.5%	1
East Asiangrpmax	72.9%	1
European (non-Finnish)	71%	1
Finnishnot grpmax-eligible	68.4%	1
Remaining individualsnot grpmax-eligible	66.9%	1
Ashkenazi Jewishnot grpmax-eligible	66.7%	2
Middle Eastern	65.4%	2
South Asian	60.9%	2
Admixed American	55.1%	2
African / African-American	37.7%	3

Amish 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: PDHX
Protein: p.Val286=
Coding: c.858T>C
MANE Select: NM_003477
dbSNP: rs497582
Type: single nucleotide variant
Location: chr11:34970180 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.13 · 5 PDB

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

Disease context

pyruvate dehydrogenase E3-binding protein 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

PDHX p.Val286Ile Uncertain significance ★ ⚠ same residue
PDHX p.Arg284Ter Pathogenic ★★ same condition
PDHX p.Arg446Ter Pathogenic/Likely pathogenic ★★ same condition
PDHX p.Arg476Ter Likely pathogenic ★★ same condition
PDHX p.Gln248Ter Pathogenic ★★ same condition
PDHX p.Gln411Ter Pathogenic/Likely pathogenic ★★ same condition
PDHX c.1023+2267A>G Uncertain significance ★★ same condition
PDHX p.Ala430Thr 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/pdhx-p-val286 (accessed [today's date]).

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