Is PRODH p.Arg431His (c.1292G>A) pathogenic?

PRODH p.Arg431His (c.1292G>A) is classified Conflicting classifications of pathogenicity in PRODH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-01). Common (popmax 14.7%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hyperprolinemia type 1.

What condition is associated with PRODH p.Arg431His (c.1292G>A)?

PRODH p.Arg431His (c.1292G>A) is associated with hyperprolinemia type 1, schizophrenia 4 (ClinVar).

How is Hyperprolinemia type 1 inherited?

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

PRODH p.Arg431His

Q: How common is PRODH p.Arg431His (c.1292G>A) in the general population?

PRODH p.Arg431His (c.1292G>A) is common (popmax 14.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1292G>A · rs2904552 · VCV4011

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 14.7%, 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	0.145	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.8	GERP 0.97, phastCons 1
Regional constraint	o/e 0.12	constrained · MANE · 23 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	19.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.7% European (non-Finnish) · 13,033/88,734 alleles

Filtering AF 14.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.4%

Overall 10.1% 17,585/174,084 alleles · common exomes 17,301/168,500 · genomes 284/5,584 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	50%	2
European (non-Finnish)grpmax	14.7%	7
Ashkenazi Jewishnot grpmax-eligible	13.7%	7
Remaining individualsnot grpmax-eligible	11%	9
Middle Eastern	9.81%	10
Finnishnot grpmax-eligible	6.73%	15
Admixed American	6.69%	15
South Asian	5.15%	19
African / African-American	3.07%	33
East Asian	0.0627%	1,594

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg431His
Coding: c.1292G>A
MANE Select: NM_016335
dbSNP: rs2904552
Type: single nucleotide variant
Location: chr22:18918451 (GRCh38)
Structure: AlphaFold pLDDT 85.29
Residue 431: a UniProt-annotated variant site (in hyrpro1; benign; moderate reduction of enzymatic 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

Also linked: schizophrenia 4

For Hyperprolinemia type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

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
PRODH p.Ala140Thr 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-arg431his (accessed [today's date]).

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