Is PRODH p.Asp426= (c.1278C>T) pathogenic?

PRODH p.Asp426= (c.1278C>T) is classified Benign/Likely benign in PRODH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 30.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hyperprolinemia type 1.

What condition is associated with PRODH p.Asp426= (c.1278C>T)?

PRODH p.Asp426= (c.1278C>T) 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.Asp426=

Q: How common is PRODH p.Asp426= (c.1278C>T) in the general population?

PRODH p.Asp426= (c.1278C>T) is common (popmax 30.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1278C>T · rs16983466 · VCV1166601

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 30.2%, mid) — 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.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.8	GERP -4.2
Overall
CADD	0.194	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 30.2% Middle Eastern · 251/832 alleles

Filtering AF 27.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 25.9%

Overall 21.7% 34,307/157,902 alleles · common exomes 33,724/154,810 · genomes 583/3,092 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	33.4%	3
Middle Easterngrpmax	30.2%	3
Admixed American	27%	4
European (non-Finnish)	25.6%	4
Ashkenazi Jewishnot grpmax-eligible	24.6%	4
Remaining individualsnot grpmax-eligible	22.3%	4
African / African-American	16.7%	6
Amishnot grpmax-eligible	16.7%	6
South Asian	11.6%	9
East Asian	10.3%	10

Finnish 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.Asp426=
Coding: c.1278C>T
MANE Select: NM_016335
dbSNP: rs16983466
Type: single nucleotide variant
Location: chr22:18918465 (GRCh38)
Structure: AlphaFold pLDDT 85.29
Residue 426: a UniProt-annotated variant site (in hyrpro1; 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 p.Asp426Glu Uncertain significance ★ 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-asp426 (accessed [today's date]).

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