Is PDHA1 p.Val8Ile (c.22G>A) pathogenic?

PDHA1 p.Val8Ile (c.22G>A) is classified Uncertain significance in PDHA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-16). AlphaMissense: likely benign (0.1109); Very rare (popmax 0.00201%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDHA1 p.Val8Ile (c.22G>A)?

PDHA1 p.Val8Ile (c.22G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PDHA1 p.Val8Ile (c.22G>A) in the general population?

PDHA1 p.Val8Ile (c.22G>A) is very rare (popmax 0.00201%, nfe) (gnomAD).

What do computational predictors say about PDHA1 p.Val8Ile (c.22G>A)?

AlphaMissense predicts likely benign (score 0.1109) — an in-silico prediction, not a clinical call.

PDHA1 p.Val8Ile

c.22G>A · rs2519332616 · VCV2336231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00201%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1109	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 5,953 bp · p 0.84 · regional, not allelic
Overall
CADD	15.73	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 0.00201% European (non-Finnish) · 18/894,380 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 19/1,093,977 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00201%	49,688
South Asian	0.00176%	56,660

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.Val8Ile
Coding: c.22G>A
MANE Select: NM_000284
dbSNP: rs2519332616
Type: single nucleotide variant
Location: chrX:19344059 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDHA1 p.Arg263Ter Pathogenic ★★ same condition
PDHA1 p.Gly291Arg Pathogenic/Likely pathogenic ★★ same condition
PDHA1 p.Pro217Leu Pathogenic ★★ same condition
PDHA1 p.Val167Met Pathogenic/Likely pathogenic ★★ same condition
PDHA1 p.Arg28Cys Uncertain significance ★★ ⚠ same condition
PDHA1 p.Arg45Trp Uncertain significance ★★ ⚠ same condition
PDHA1 p.Arg88His Uncertain significance ★★ ⚠ same condition
PDHA1 p.Lys40Glu Uncertain significance ★★ ⚠ 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-val8ile (accessed [today's date]).

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