Is PRODH p.Pro19Gln (c.56C>A) pathogenic?

PRODH p.Pro19Gln (c.56C>A) is classified Benign/Likely benign in PRODH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hyperprolinemia type 1.

What condition is associated with PRODH p.Pro19Gln (c.56C>A)?

PRODH p.Pro19Gln (c.56C>A) is associated with hyperprolinemia type 1 (ClinVar).

How is Hyperprolinemia type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PRODH p.Pro19Gln

Q: How common is PRODH p.Pro19Gln (c.56C>A) in the general population?

PRODH p.Pro19Gln (c.56C>A) is common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.56C>A · rs2008720 · VCV1168807

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

hyperprolinemia type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.005	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -1.9
Regional constraint	o/e 0.12	constrained · MANE · 23 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	2.842	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% European (non-Finnish) · 2/2 alleles

Filtering AF 17.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.43%

Overall 75% 6/8 alleles · common

Ancestry group	Frequency	1 in
East Asian	100%	1
European (non-Finnish)grpmax	100%	1
African / African-American	50%	2
Remaining individualsnot grpmax-eligible	50%	2

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: PRODH
Protein: p.Pro19Gln
Coding: c.56C>A
MANE Select: NM_016335
dbSNP: rs2008720
Type: single nucleotide variant
Location: chr22:18936232 (GRCh38)
Structure: AlphaFold pLDDT 85.29
Residue 19: a UniProt-annotated variant site (increased proline dehydrogenase activity)

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

Disease context

hyperprolinemia type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperprolinemia type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

PRODH p.Pro19= Likely benign ★ same residue
PRODH c.1104+2T>C Likely pathogenic ★★ same condition
PRODH p.Gln59Ter Pathogenic/Likely pathogenic ★★ same condition
PRODH p.Tyr412Ter Pathogenic ★★ same condition
PRODH c.1427+4C>T Uncertain significance ★★ same condition
PRODH c.1615+1G>C Uncertain significance ★★ same condition
PRODH c.482+6G>A Uncertain significance ★★ same condition
PRODH c.929+3G>A 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/prodh-p-pro19gln (accessed [today's date]).

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