Is PDHA1 p.Ala265= (c.795A>G) pathogenic?

PDHA1 p.Ala265= (c.795A>G) is classified Benign in PDHA1 (ClinVar, Expert panel, 12 submitters; last evaluated 2021-05-05). Common (popmax 85.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with pyruvate dehydrogenase deficiency.

What condition is associated with PDHA1 p.Ala265= (c.795A>G)?

PDHA1 p.Ala265= (c.795A>G) is associated with pyruvate dehydrogenase deficiency, pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How is Pyruvate dehydrogenase deficiency inherited?

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

PDHA1 p.Ala265=

Q: How common is PDHA1 p.Ala265= (c.795A>G) in the general population?

PDHA1 p.Ala265= (c.795A>G) is common (popmax 85.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.795A>G · rs1126565 · VCV92772

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 85.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

pyruvate dehydrogenase deficiency

ClinGen expert panel — Mitochondrial Diseases VCEP

Benign for pyruvate dehydrogenase deficiency. Applied ACMG criteria (verbatim):

BS2 BP7 BA1

Curation rationale (ClinGen, verbatim)

The allele frequency of the c.795A>G variant in the PDHA1 gene is 13.1% in gnomAD, including more than 9,000 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD- BA1; >16 hemizygotes- BS2). Furthermore, splicing predictors (SPLICE AI) do not predict a deleterious effect (BP7). In summary, this synonymous variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 -0.95	GERP -3.9
Overall
CADD	2.668	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 85.1% African / African-American · 48,505/56,999 alleles

Filtering AF 84.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 84.2%

Overall 8.55% 103,223/1,207,089 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	85.1%	1
Middle Eastern	18.6%	5
South Asian	15.5%	6
Amishnot grpmax-eligible	11.6%	9
Remaining individualsnot grpmax-eligible	11.4%	9
Ashkenazi Jewishnot grpmax-eligible	11.1%	9
Admixed American	8.94%	11
Finnishnot grpmax-eligible	3.51%	28
European (non-Finnish)	3.5%	29
East Asian	0.48%	209

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.Ala265=
Coding: c.795A>G
MANE Select: NM_000284
dbSNP: rs1126565
Type: single nucleotide variant
Location: chrX:19355721 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 265: an α-helix

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

Disease context

pyruvate dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate dehydrogenase E1-alpha deficiency

For Pyruvate dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive, Not applicable, X-linked dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

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.Glu333Asp Benign ★★★ same condition
PDHA1 p.Met282Leu Benign ★★★ same condition
PDHA1 c.292-1G>A 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-ala265 (accessed [today's date]).

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