Is PRODH p.Arg577Trp (c.1729C>T) pathogenic?

PRODH p.Arg577Trp (c.1729C>T) is classified Conflicting classifications of pathogenicity in PRODH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-12-02). Ultra-rare (popmax 0.0108%, sas); Associated with Inborn genetic diseases.

What condition is associated with PRODH p.Arg577Trp (c.1729C>T)?

PRODH p.Arg577Trp (c.1729C>T) is associated with Inborn genetic diseases, hyperprolinemia type 1, schizophrenia 4 (ClinVar).

How common is PRODH p.Arg577Trp (c.1729C>T) in the general population?

PRODH p.Arg577Trp (c.1729C>T) is ultra-rare (popmax 0.0108%, sas) (gnomAD).

PRODH p.Arg577Trp

c.1729C>T · rs184218784 · VCV1214571

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.235	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 3.7, phastCons 0.12
Regional constraint	o/e 0.12	constrained · MANE · 23 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0108% South Asian · 3/27,670 alleles

Filtering AF 0.00287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0015%

Overall 0.0132% 71/536,024 alleles · ultra-rare exomes 65/504,300 · genomes 6/31,724 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.294%	340
South Asiangrpmax	0.0108%	9,223
African / African-American	0.00291%	34,376
European (non-Finnish)	0.00129%	77,814

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.Arg577Trp
Coding: c.1729C>T
MANE Select: NM_016335
dbSNP: rs184218784
Type: single nucleotide variant
Location: chr22:18913249 (GRCh38)
Structure: AlphaFold pLDDT 85.29

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperprolinemia type 1 schizophrenia 4

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-arg577trp (accessed [today's date]).

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