Is PDHB p.Ser5Pro (c.13T>C) pathogenic?

PDHB p.Ser5Pro (c.13T>C) is classified Uncertain significance in PDHB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-08). AlphaMissense: likely benign (0.0914); Ultra-rare (popmax 0.0659%, mid); Associated with Inborn genetic diseases.

What condition is associated with PDHB p.Ser5Pro (c.13T>C)?

PDHB p.Ser5Pro (c.13T>C) is associated with Inborn genetic diseases, pyruvate dehydrogenase E1-beta deficiency (ClinVar).

How common is PDHB p.Ser5Pro (c.13T>C) in the general population?

PDHB p.Ser5Pro (c.13T>C) is ultra-rare (popmax 0.0659%, mid) (gnomAD).

What do computational predictors say about PDHB p.Ser5Pro (c.13T>C)?

AlphaMissense predicts likely benign (score 0.0914) — an in-silico prediction, not a clinical call.

PDHB p.Ser5Pro

c.13T>C · rs200470565 · VCV2185612

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0914 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0659%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0914	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -7.88	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 1	GERP -3, phastCons 0.071
Regional constraint	o/e 1.38	unconstrained · MANE · 175 bp · p 0.014 · regional, not allelic
Overall
CADD	17.09	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 0.0659% Middle Eastern · 4/6,068 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.0241% 388/1,611,596 alleles · ultra-rare exomes 367/1,459,406 · genomes 21/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0659%	1,517
European (non-Finnish)	0.0298%	3,360
Remaining individualsnot grpmax-eligible	0.016%	6,233
Finnishnot grpmax-eligible	0.0159%	6,290
African / African-American	0.00801%	12,480
South Asian	0.00551%	18,154
Admixed American	0.00334%	29,940

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.Ser5Pro
Coding: c.13T>C
MANE Select: NM_000925
dbSNP: rs200470565
Type: single nucleotide variant
Location: chr3:58433797 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 94.18 · 9 PDB

Full PDHB 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

Also linked: pyruvate dehydrogenase E1-beta deficiency

Similar variants

PDHB p.Ser5Tyr Uncertain significance ★ ⚠ same residue
PDHB p.Ser5= Likely benign ★ same residue
PDHB c.934+1G>A Likely pathogenic ★★ same condition
PDHB p.Arg71Ter Pathogenic/Likely pathogenic ★★ same condition
PDHB p.Gln118Ter Likely pathogenic ★★ same condition
PDHB p.Met101Val Pathogenic ★★ ⚠ same condition
PDHB p.Ala150Ser Uncertain significance ★★ ⚠ same condition
PDHB p.Ala314Val 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/pdhb-p-ser5pro (accessed [today's date]).

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