Is PDHA1 p.Phe375fs (c.1125del) pathogenic?

PDHA1 p.Phe375fs (c.1125del) is classified Pathogenic in PDHA1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-10-15). Associated with pyruvate dehydrogenase E1-alpha deficiency.

What condition is associated with PDHA1 p.Phe375fs (c.1125del)?

PDHA1 p.Phe375fs (c.1125del) is associated with 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.Phe375fs

c.1125del · VCV4070464

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

pyruvate dehydrogenase E1-alpha deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: PDHA1
Protein: p.Phe375fs
Coding: c.1125del
MANE Select: NM_000284
Type: Deletion
Location: chrX:19359602 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 375: 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.Phe375_Arg378delinsCys Pathogenic same residue
PDHA1 p.Phe375_Glu376insLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPhe Pathogenic same residue
PDHA1 c.1009-16_1010del Pathogenic/Likely pathogenic ★★ same condition
PDHA1 c.1011_1034del Pathogenic/Likely pathogenic ★★ same condition
PDHA1 c.1008+1_1008+27del Pathogenic ★ same condition
PDHA1 p.Arg343fs Pathogenic ★ same condition
PDHA1 p.Arg378fs Pathogenic ★ same condition
PDHA1 p.Asp348fs 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-phe375fs (accessed [today's date]).

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