Is OCRL p.Glu125Asp (c.375G>T) pathogenic?

OCRL p.Glu125Asp (c.375G>T) is classified Benign/Likely benign in OCRL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.079); Rare (popmax 0.868%, sas); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with OCRL p.Glu125Asp (c.375G>T)?

OCRL p.Glu125Asp (c.375G>T) is associated with Nephrolithiasis/nephrocalcinosis, intellectual disability, Dent disease type 2 (ClinVar).

How common is OCRL p.Glu125Asp (c.375G>T) in the general population?

OCRL p.Glu125Asp (c.375G>T) is rare (popmax 0.868%, sas) (gnomAD).

What do computational predictors say about OCRL p.Glu125Asp (c.375G>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

OCRL p.Glu125Asp

c.375G>T · rs773022942 · VCV589078

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.868%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP -0.058, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 19 kb · p 0.85 · regional, not allelic
Overall
CADD	15.22	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.868% South Asian · 492/56,651 alleles

Filtering AF 0.805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.78%

Overall 0.0437% 526/1,202,302 alleles · rare exomes 499/1,090,020 · genomes 27/112,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.868%	115
Middle Eastern	0.0692%	1,444
Remaining individualsnot grpmax-eligible	0.0591%	1,692
European (non-Finnish)	0.000338%	295,968

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: OCRL
Protein: p.Glu125Asp
Coding: c.375G>T
MANE Select: NM_000276
dbSNP: rs773022942
Type: single nucleotide variant
Location: chrX:129557886 (GRCh38)
Structure: AlphaFold pLDDT 82.91 · 5 PDB

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

Disease context

Nephrolithiasis/nephrocalcinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability Dent disease type 2 oculocerebrorenal syndrome congenital myopathy

Similar variants

OCRL c.1244+1G>A Pathogenic/Likely pathogenic ★★ same condition
OCRL c.1714-1G>A Pathogenic ★★ same condition
OCRL c.2256+1G>T Likely pathogenic ★★ same condition
OCRL c.560+1G>C Pathogenic/Likely pathogenic ★★ same condition
OCRL c.940-11G>A Pathogenic/Likely pathogenic ★★ same condition
OCRL p.Ala861Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
OCRL p.Arg318Cys Pathogenic/Likely pathogenic ★★ same condition
OCRL p.Arg318His Pathogenic/Likely pathogenic ★★ 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/ocrl-p-glu125asp (accessed [today's date]).

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