Is PDHA1 p.Val71Ile (c.211G>A) pathogenic?

PDHA1 p.Val71Ile (c.211G>A) is classified Likely benign in PDHA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). AlphaMissense: likely benign (0.0666); Very rare (popmax 0.00135%, nfe); Associated with pyruvate dehydrogenase E1-alpha deficiency.

What condition is associated with PDHA1 p.Val71Ile (c.211G>A)?

PDHA1 p.Val71Ile (c.211G>A) is associated with pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How common is PDHA1 p.Val71Ile (c.211G>A) in the general population?

PDHA1 p.Val71Ile (c.211G>A) is very rare (popmax 0.00135%, nfe) (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.Val71Ile (c.211G>A)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

PDHA1 p.Val71Ile

c.211G>A · rs957121684 · VCV2957233

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pyruvate dehydrogenase E1-alpha deficiency

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -1.92	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 6.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 5,444 bp · p 1.2e-20 · regional, not allelic
Overall
CADD	16.61	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 0.00135% European (non-Finnish) · 12/887,855 alleles

Filtering AF 0.000721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000569%

Overall 0.000998% 12/1,201,898 alleles · very rare exomes 11/1,090,002 · genomes 1/111,896 · joint denominator

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.Val71Ile
Coding: c.211G>A
MANE Select: NM_000284
dbSNP: rs957121684
Type: single nucleotide variant
Location: chrX:19350030 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 71: 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.Val71Ala 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
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-val71ile (accessed [today's date]).

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