Is PDHA1 p.Pro373Ser (c.1117C>T) pathogenic?

PDHA1 p.Pro373Ser (c.1117C>T) is classified Uncertain significance in PDHA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-22). AlphaMissense: likely benign (0.0891); Very rare (popmax 0.00176%, sas); Associated with pyruvate dehydrogenase E1-alpha deficiency.

What condition is associated with PDHA1 p.Pro373Ser (c.1117C>T)?

PDHA1 p.Pro373Ser (c.1117C>T) is associated with pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How common is PDHA1 p.Pro373Ser (c.1117C>T) in the general population?

PDHA1 p.Pro373Ser (c.1117C>T) is very rare (popmax 0.00176%, sas) (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.Pro373Ser (c.1117C>T)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

PDHA1 p.Pro373Ser

c.1117C>T · VCV3891935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pyruvate dehydrogenase E1-alpha deficiency

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.44	indeterminate
SaProt	LLR -8.36	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 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 711 bp · p 0.5 · regional, not allelic
Overall
CADD	17.09	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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% South Asian · 1/56,967 alleles

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

Overall 0.000455% 5/1,097,788 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00176%	56,967
European (non-Finnish)	0.000447%	223,781

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.Pro373Ser
Coding: c.1117C>T
MANE Select: NM_000284
Type: single nucleotide variant
Location: chrX:19359597 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB

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.Pro373_Glu376del Uncertain significance ★ same residue
PDHA1 p.Pro373_Pro374insGluLeuGlyTyrHisIleTyrSerSerAspPro Pathogenic same residue
PDHA1 p.Pro373_Pro374insTer Pathogenic same residue
PDHA1 p.Pro373_Pro374insTyrHisIleTyrSerSerAspPro Likely pathogenic same residue
PDHA1 p.Pro373fs Pathogenic same residue
PDHA1 p.Ala169Val Pathogenic ★★★ same condition
PDHA1 p.Arg304Ter Pathogenic ★★★ same condition
PDHA1 p.Arg378Cys 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-pro373ser (accessed [today's date]).

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