Is PDHA1 p.Val262Phe (c.784G>T) pathogenic?

PDHA1 p.Val262Phe (c.784G>T) is classified Uncertain significance in PDHA1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.9856); Absent from gnomAD v4.1; Associated with pyruvate dehydrogenase E1-alpha deficiency.

What condition is associated with PDHA1 p.Val262Phe (c.784G>T)?

PDHA1 p.Val262Phe (c.784G>T) is associated with pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How common is PDHA1 p.Val262Phe (c.784G>T) in the general population?

PDHA1 p.Val262Phe (c.784G>T) 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.Val262Phe (c.784G>T)?

AlphaMissense predicts likely pathogenic (score 0.9856) — an in-silico prediction, not a clinical call.

PDHA1 p.Val262Phe

c.784G>T · rs202166915 · VCV2138485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9856 · 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	0.9856	likely pathogenic
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -15.52	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 2,237 bp · p 0.011 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Val262Phe
Coding: c.784G>T
MANE Select: NM_000284
dbSNP: rs202166915
Type: single nucleotide variant
Location: chrX:19355710 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 262: an α-helix

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.Val262Ile Benign/Likely benign ★★ ⚠ same residue
PDHA1 p.Val262Leu Likely 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
PDHA1 p.Ile280Ser Uncertain significance ★★★ ⚠ same condition
PDHA1 p.Ala265= 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-val262phe (accessed [today's date]).

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