Is PDK4 p.Phe234Val (c.700T>G) pathogenic?

PDK4 p.Phe234Val (c.700T>G) is classified Uncertain significance in PDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-20). AlphaMissense: likely benign (0.0629); Ultra-rare (popmax 0.0202%, sas).

How common is PDK4 p.Phe234Val (c.700T>G) in the general population?

PDK4 p.Phe234Val (c.700T>G) is ultra-rare (popmax 0.0202%, sas) (gnomAD).

What do computational predictors say about PDK4 p.Phe234Val (c.700T>G)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

PDK4 p.Phe234Val

c.700T>G · VCV3305547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -4.90	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 2.4	GERP -0.87, phastCons 0.54
Regional constraint	o/e 0.99	unconstrained · MANE · 11 kb · p 0.81 · regional, not allelic
Overall
CADD	15.68	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 0.0202% South Asian · 18/89,000 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.00116% 18/1,549,152 alleles · ultra-rare exomes 16/1,396,926 · genomes 2/152,226 · 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: PDK4
Protein: p.Phe234Val
Coding: c.700T>G
MANE Select: NM_002612
Type: single nucleotide variant
Location: chr7:95589711 (GRCh38)
Gene constraint: LOEUF 1.244 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.68 · 8 PDB
Residue 234: the histidine kinase domain; a β-strand

Full PDK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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PDK4 p.Arg166His Uncertain significance ★ ⚠ same type
PDK4 p.Arg323Gln Uncertain significance ★ ⚠ same type
PDK4 p.Arg323Leu Uncertain significance ★ ⚠ same type
PDK4 p.Arg323Trp Uncertain significance ★ ⚠ same type
PDK4 p.Arg58Ter Uncertain significance ★ same type

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/pdk4-p-phe234val (accessed [today's date]).

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