Is OCRL p.Arg25Pro (c.74G>C) pathogenic?

OCRL p.Arg25Pro (c.74G>C) is classified Uncertain significance in OCRL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-26). AlphaMissense: likely benign (0.2756); Very rare (popmax 0.000783%, nfe); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with OCRL p.Arg25Pro (c.74G>C)?

OCRL p.Arg25Pro (c.74G>C) is associated with Nephrolithiasis/nephrocalcinosis, oculocerebrorenal syndrome (ClinVar).

How common is OCRL p.Arg25Pro (c.74G>C) in the general population?

OCRL p.Arg25Pro (c.74G>C) is very rare (popmax 0.000783%, nfe) (gnomAD).

What do computational predictors say about OCRL p.Arg25Pro (c.74G>C)?

AlphaMissense predicts likely benign (score 0.2756) — an in-silico prediction, not a clinical call.

OCRL p.Arg25Pro

c.74G>C · rs368472232 · VCV2779810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000783%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.2756	likely benign
REVEL	0.555	indeterminate
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.73, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 19 kb · p 0.85 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000783% European (non-Finnish) · 7/894,058 alleles

Filtering AF 0.000326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000579% 7/1,208,458 alleles · very rare exomes 6/1,097,188 · genomes 1/111,270 · joint denominator

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.Arg25Pro
Coding: c.74G>C
MANE Select: NM_000276
dbSNP: rs368472232
Type: single nucleotide variant
Location: chrX:129540778 (GRCh38)
Structure: AlphaFold pLDDT 82.91 · 5 PDB
Residue 25: the ph domain; a β-strand

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: oculocerebrorenal syndrome

Similar variants

OCRL p.Arg25= Likely benign ★ same residue
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

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-arg25pro (accessed [today's date]).

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