Is PDHA1 p.Asp33Val (c.98A>T) pathogenic?

PDHA1 p.Asp33Val (c.98A>T) is classified Conflicting classifications of pathogenicity in PDHA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-09-19). AlphaMissense: likely benign (0.1932); Very rare (popmax 0.00176%, afr); Associated with pyruvate dehydrogenase E1-alpha deficiency.

What condition is associated with PDHA1 p.Asp33Val (c.98A>T)?

PDHA1 p.Asp33Val (c.98A>T) is associated with pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How common is PDHA1 p.Asp33Val (c.98A>T) in the general population?

PDHA1 p.Asp33Val (c.98A>T) is very rare (popmax 0.00176%, afr) (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.Asp33Val (c.98A>T)?

AlphaMissense predicts likely benign (score 0.1932) — an in-silico prediction, not a clinical call.

PDHA1 p.Asp33Val

c.98A>T · rs752678074 · VCV1708453

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pyruvate dehydrogenase E1-alpha deficiency

Computational evidence

Protein change
AlphaMissense	0.1932	likely benign
REVEL	0.635	indeterminate
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 5,953 bp · p 0.84 · regional, not allelic
Overall
CADD	24.0	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 0.00176% African / African-American · 1/56,760 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000827%

Overall 0.00136% 16/1,174,914 alleles · very rare exomes 12/1,062,463 · genomes 4/112,451 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00176%	56,760
European (non-Finnish)	0.00174%	57,541

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.Asp33Val
Coding: c.98A>T
MANE Select: NM_000284
dbSNP: rs752678074
Type: single nucleotide variant
Location: chrX:19349352 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 33: a β-strand

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.Asp33His Benign/Likely benign ★★ ⚠ 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
PDHA1 p.Glu333Asp 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-asp33val (accessed [today's date]).

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