Is PDHX p.Phe445Val (c.1333T>G) pathogenic?

PDHX p.Phe445Val (c.1333T>G) is classified Benign/Likely benign in PDHX (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1079); Rare (popmax 0.783%, sas); Associated with pyruvate dehydrogenase E3-binding protein deficiency.

What condition is associated with PDHX p.Phe445Val (c.1333T>G)?

PDHX p.Phe445Val (c.1333T>G) is associated with pyruvate dehydrogenase E3-binding protein deficiency (ClinVar).

How common is PDHX p.Phe445Val (c.1333T>G) in the general population?

PDHX p.Phe445Val (c.1333T>G) is rare (popmax 0.783%, 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 PDHX p.Phe445Val (c.1333T>G)?

AlphaMissense predicts likely benign (score 0.1079) — an in-silico prediction, not a clinical call.

PDHX p.Phe445Val

c.1333T>G · rs147948716 · VCV214959

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1079 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.783%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate dehydrogenase E3-binding protein deficiency

Computational evidence

Protein change
AlphaMissense	0.1079	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -2.66	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 4.2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 79 kb · p 0.93 · regional, not allelic
Overall
CADD	22.3	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 0.783% South Asian · 713/91,070 alleles

Filtering AF 0.735% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.716%

Overall 0.0688% 1,111/1,613,908 alleles · rare exomes 1,046/1,461,756 · genomes 65/152,152 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.783%	128
Middle Eastern	0.264%	379
Ashkenazi Jewishnot grpmax-eligible	0.108%	925
Remaining individualsnot grpmax-eligible	0.072%	1,389
Admixed American	0.03%	3,333
European (non-Finnish)	0.0238%	4,199
Finnishnot grpmax-eligible	0.00781%	12,802
African / African-American	0.00133%	74,998

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: PDHX
Protein: p.Phe445Val
Coding: c.1333T>G
MANE Select: NM_003477
dbSNP: rs147948716
Type: single nucleotide variant
Location: chr11:34994999 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.13 · 5 PDB

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

Disease context

pyruvate dehydrogenase E3-binding protein 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

PDHX p.Phe445= Likely benign ★ same residue
PDHX p.Arg284Ter Pathogenic ★★ same condition
PDHX p.Arg446Ter Pathogenic/Likely pathogenic ★★ same condition
PDHX p.Arg476Ter Likely pathogenic ★★ same condition
PDHX p.Gln248Ter Pathogenic ★★ same condition
PDHX p.Gln411Ter Pathogenic/Likely pathogenic ★★ same condition
PDHX c.1023+2267A>G Uncertain significance ★★ same condition
PDHX p.Ala430Thr 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/pdhx-p-phe445val (accessed [today's date]).

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