Is OPLAH p.Phe612= (c.1836T>C) pathogenic?

OPLAH p.Phe612= (c.1836T>C) is classified Benign in OPLAH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Common (popmax 35.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with 5-oxoprolinase deficiency.

What condition is associated with OPLAH p.Phe612= (c.1836T>C)?

OPLAH p.Phe612= (c.1836T>C) is associated with 5-oxoprolinase deficiency (ClinVar).

How is 5-oxoprolinase deficiency inherited?

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

OPLAH p.Phe612=

Q: How common is OPLAH p.Phe612= (c.1836T>C) in the general population?

OPLAH p.Phe612= (c.1836T>C) is common (popmax 35.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1836T>C · rs11993554 · VCV1165138

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 35.4%, afr) — too common for a highly-penetrant pathogenic allele

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 -4	GERP -3.6
Overall
CADD	0.141	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.4% African / African-American · 26,526/74,986 alleles

Filtering AF 35% ClinGen BA1/BS1 input FAF95, joint · FAF99 34.9%

Overall 8.92% 143,845/1,612,122 alleles · common exomes 120,865/1,459,964 · genomes 22,980/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	35.4%	3
Middle Eastern	11.6%	9
Remaining individualsnot grpmax-eligible	8.99%	11
Finnishnot grpmax-eligible	8.04%	12
European (non-Finnish)	7.98%	13
Amishnot grpmax-eligible	7.68%	13
Ashkenazi Jewishnot grpmax-eligible	6.69%	15
Admixed American	6.6%	15
South Asian	6.25%	16
East Asian	0.406%	246

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.Phe612=
Coding: c.1836T>C
MANE Select: NM_017570
dbSNP: rs11993554
Type: single nucleotide variant
Location: chr8:144056626 (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-phe612 (accessed [today's date]).

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