Is PDHA1 p.Val233= (c.699T>C) pathogenic?

PDHA1 p.Val233= (c.699T>C) is classified Likely benign in PDHA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-03). Very rare (popmax 0.000447%, nfe); Associated with pyruvate dehydrogenase E1-alpha deficiency.

What condition is associated with PDHA1 p.Val233= (c.699T>C)?

PDHA1 p.Val233= (c.699T>C) is associated with pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How common is PDHA1 p.Val233= (c.699T>C) in the general population?

PDHA1 p.Val233= (c.699T>C) is very rare (popmax 0.000447%, nfe) (gnomAD).

How is Pyruvate dehydrogenase deficiency inherited?

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

PDHA1 p.Val233=

c.699T>C · rs1279461531 · VCV1631957

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Conditions

pyruvate dehydrogenase E1-alpha deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.3	GERP -3.9
Overall
CADD	3.525	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000447% European (non-Finnish) · 4/895,069 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.00033% 4/1,210,621 alleles · very rare exomes 3/1,097,770 · genomes 1/112,851 · joint denominator

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: PDHA1
Protein: p.Val233=
Coding: c.699T>C
MANE Select: NM_000284
dbSNP: rs1279461531
Type: single nucleotide variant
Location: chrX:19355444 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 233: an α-helix

Full PDHA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pyruvate dehydrogenase E1-alpha 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

PDHA1 p.Val233Ala Uncertain significance ★ ⚠ same residue
PDHA1 p.Val233Ile Uncertain significance ★ ⚠ same residue
PDHA1 p.Ala169Val Pathogenic ★★★ same condition
PDHA1 p.Arg304Ter Pathogenic ★★★ same condition
PDHA1 p.Arg378Cys Pathogenic ★★★ ⚠ same condition
PDHA1 p.Arg72Cys Likely pathogenic ★★★ same condition
PDHA1 p.Ile280Ser Uncertain significance ★★★ ⚠ same condition
PDHA1 p.Ala265= Benign ★★★ 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/pdha1-p-val233 (accessed [today's date]).

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