Is PDHA1 p.Arg288Ser (c.862C>A) pathogenic?

PDHA1 p.Arg288Ser (c.862C>A) is classified Pathogenic in PDHA1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with pyruvate dehydrogenase E1-alpha deficiency.

What condition is associated with PDHA1 p.Arg288Ser (c.862C>A)?

PDHA1 p.Arg288Ser (c.862C>A) is associated with pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How common is PDHA1 p.Arg288Ser (c.862C>A) in the general population?

PDHA1 p.Arg288Ser (c.862C>A) is absent from gnomAD v4.1 (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 PDHA1 p.Arg288Ser (c.862C>A)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

PDHA1 p.Arg288Ser

c.862C>A · VCV4070377

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate dehydrogenase E1-alpha deficiency

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 3% in PDHA1
REVEL	0.982	strongly pathogenic-leaning
SaProt	LLR -15.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.09	constrained · MANE · 1,263 bp · p 2e-05 · regional, not allelic
Overall
CADD	28.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDHA1
Protein: p.Arg288Ser
Coding: c.862C>A
MANE Select: NM_000284
Type: single nucleotide variant
Location: chrX:19357682 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 288: a UniProt-annotated variant site (in pdhad)

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.Arg288Cys Pathogenic/Likely pathogenic ★★ same residue
PDHA1 p.Arg288His Pathogenic ★★ same residue
PDHA1 p.Arg288Leu Likely pathogenic same residue
PDHA1 p.Arg288fs Pathogenic 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

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-arg288ser (accessed [today's date]).

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