Is PDX1 p.Pro46= (c.138G>A) pathogenic?

PDX1 p.Pro46= (c.138G>A) is classified Likely benign in PDX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). Very rare (popmax 0.00835%, afr); Associated with maturity-onset diabetes of the young.

What condition is associated with PDX1 p.Pro46= (c.138G>A)?

PDX1 p.Pro46= (c.138G>A) is associated with maturity-onset diabetes of the young (ClinVar).

How common is PDX1 p.Pro46= (c.138G>A) in the general population?

PDX1 p.Pro46= (c.138G>A) is very rare (popmax 0.00835%, afr) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

PDX1 p.Pro46=

c.138G>A · VCV4134354

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00835%, afr)

Conditions

maturity-onset diabetes of the young

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -2.7, phastCons 0.97
Overall
CADD	7.787	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00835% African / African-American · 6/71,838 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00246%

Overall 0.000519% 8/1,540,574 alleles · very rare exomes 5/1,388,434 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00835%	11,973
Admixed American	0.00199%	50,316
European (non-Finnish)	8.75e-05%	1,143,054

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: PDX1
Protein: p.Pro46=
Coding: c.138G>A
MANE Select: NM_000209
Type: single nucleotide variant
Location: chr13:27920276 (GRCh38)
Gene constraint: LOEUF 1.642 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.99 · 2 PDB
Residue 46: the 'transactivation domain' region; the 'disordered' region

Full PDX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

maturity-onset diabetes of the young — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PDX1 p.Ala10Thr Uncertain significance ★★ ⚠ same condition
PDX1 p.Asp226Ala Uncertain significance ★★ ⚠ same condition
PDX1 p.Ile190Thr Uncertain significance ★★ ⚠ same condition
PDX1 p.Ala275= Likely benign ★★ same condition
PDX1 p.Arg176= Likely benign ★★ same condition
PDX1 p.Asn113= Likely benign ★★ same condition
PDX1 p.Asn2= Benign/Likely benign ★★ same condition
PDX1 p.Leu166= Benign/Likely benign ★★ 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/pdx1-p-pro46 (accessed [today's date]).

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