Is PDHB p.Leu289Pro (c.866T>C) pathogenic?

PDHB p.Leu289Pro (c.866T>C) is classified Uncertain significance in PDHB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-01). AlphaMissense: likely pathogenic (0.9966); Very rare (popmax 0.0011%, nfe).

How common is PDHB p.Leu289Pro (c.866T>C) in the general population?

PDHB p.Leu289Pro (c.866T>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about PDHB p.Leu289Pro (c.866T>C)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

PDHB p.Leu289Pro

c.866T>C · rs371393276 · VCV1675926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic · top 6% in PDHB
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -14.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,820 bp · p 5.1e-06 · regional, not allelic
Overall
CADD	28.1	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

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,894 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,613,934 alleles · very rare exomes 12/1,461,726 · genomes 1/152,208 · 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: PDHB
Protein: p.Leu289Pro
Coding: c.866T>C
MANE Select: NM_000925
dbSNP: rs371393276
Type: single nucleotide variant
Location: chr3:58428541 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 94.18 · 9 PDB
Residue 289: a β-strand

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

Similar variants

PDHB c.934+1G>A Likely pathogenic ★★ same type
PDHB p.Arg71Ter Pathogenic/Likely pathogenic ★★ same type
PDHB p.Gln118Ter Likely pathogenic ★★ same type
PDHB p.Met101Val Pathogenic ★★ ⚠ same type
PDHB p.Ala150Ser Uncertain significance ★★ ⚠ same type
PDHB p.Ala314Val Uncertain significance ★★ ⚠ same type
PDHB p.Arg71Gln Uncertain significance ★★ same type
PDHB p.Asn194Lys 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/pdhb-p-leu289pro (accessed [today's date]).

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