Is OPLAH p.Pro126= (c.378T>G) pathogenic?

OPLAH p.Pro126= (c.378T>G) is classified Likely benign in OPLAH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Ultra-rare (popmax 0.0242%, nfe); Associated with 5-oxoprolinase deficiency.

What condition is associated with OPLAH p.Pro126= (c.378T>G)?

OPLAH p.Pro126= (c.378T>G) is associated with 5-oxoprolinase deficiency (ClinVar).

How common is OPLAH p.Pro126= (c.378T>G) in the general population?

OPLAH p.Pro126= (c.378T>G) is ultra-rare (popmax 0.0242%, nfe) (gnomAD).

How is 5-oxoprolinase deficiency inherited?

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

OPLAH p.Pro126=

c.378T>G · rs1587567078 · VCV736214

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, nfe)

Conditions

5-oxoprolinase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6	GERP -3.3
Overall
CADD	2.118	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% European (non-Finnish) · 282/1,163,220 alleles

Filtering AF 0.0219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0193% 305/1,580,626 alleles · ultra-rare exomes 305/1,428,400 · genomes 0/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0242%	4,125
Middle Eastern	0.0166%	6,026
Remaining individualsnot grpmax-eligible	0.0147%	6,812
Ashkenazi Jewishnot grpmax-eligible	0.0103%	9,683
African / African-American	0.00674%	14,827
South Asian	0.00346%	28,876
Admixed American	0.00177%	56,352
Finnishnot grpmax-eligible	0.00167%	59,930

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: OPLAH
Protein: p.Pro126=
Coding: c.378T>G
MANE Select: NM_017570
dbSNP: rs1587567078
Type: single nucleotide variant
Location: chr8:144059065 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.08

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

Disease context

5-oxoprolinase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 5-oxoprolinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

OPLAH c.587+1G>A Pathogenic/Likely pathogenic ★★ same condition
OPLAH p.Gln1006Ter Pathogenic/Likely pathogenic ★★ same condition
OPLAH p.Tyr248Ter Likely pathogenic ★★ same condition
OPLAH p.Ala1093Val Uncertain significance ★★ ⚠ same condition
OPLAH p.Ala344Thr Uncertain significance ★★ ⚠ same condition
OPLAH p.Ala422Val Uncertain significance ★★ ⚠ same condition
OPLAH p.Ala46Thr Uncertain significance ★★ ⚠ same condition
OPLAH p.Ala475Val 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/oplah-p-pro126 (accessed [today's date]).

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