Is PDX1 p.Pro99Ser (c.295C>T) pathogenic?

PDX1 p.Pro99Ser (c.295C>T) is classified Uncertain significance in PDX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: likely benign (0.0679); Very rare (popmax 6.33e-05%).

How common is PDX1 p.Pro99Ser (c.295C>T) in the general population?

PDX1 p.Pro99Ser (c.295C>T) is very rare (popmax 6.33e-05%) (gnomAD).

What do computational predictors say about PDX1 p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

PDX1 p.Pro99Ser

c.295C>T · VCV3768863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.33e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.422	indeterminate
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.24	unconstrained · MANE · 4,149 bp · p 0.00053 · regional, not allelic
Overall
CADD	20.9	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 6.33e-05%

Overall 6.33e-05% 1/1,579,320 alleles · very rare exomes 1/1,427,044 · genomes 0/152,276 · 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: PDX1
Protein: p.Pro99Ser
Coding: c.295C>T
MANE Select: NM_000209
Type: single nucleotide variant
Location: chr13:27920433 (GRCh38)
Gene constraint: LOEUF 1.642 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.99 · 2 PDB

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

Similar variants

PDX1 p.Pro99His Uncertain significance ★★ ⚠ same residue
PDX1 p.Glu178Lys Pathogenic/Likely pathogenic ★★ same type
PDX1 p.Lys191Gln Likely pathogenic ★★ same type
PDX1 p.Ala10Thr Uncertain significance ★★ ⚠ same type
PDX1 p.Ala152Val Uncertain significance ★★ ⚠ same type
PDX1 p.Ala34Val Uncertain significance ★★ same type
PDX1 p.Arg114Leu Uncertain significance ★★ ⚠ same type
PDX1 p.Arg148Trp 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/pdx1-p-pro99ser (accessed [today's date]).

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