Is OCRL p.Met299Ile (c.897G>A) pathogenic?

OCRL p.Met299Ile (c.897G>A) is classified Benign in OCRL (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1176); Low-frequency (popmax 4.11%, amr); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with OCRL p.Met299Ile (c.897G>A)?

OCRL p.Met299Ile (c.897G>A) is associated with Nephrolithiasis/nephrocalcinosis, oculocerebrorenal syndrome (ClinVar).

How common is OCRL p.Met299Ile (c.897G>A) in the general population?

OCRL p.Met299Ile (c.897G>A) is low-frequency (popmax 4.11%, amr) (gnomAD).

What do computational predictors say about OCRL p.Met299Ile (c.897G>A)?

AlphaMissense predicts likely benign (score 0.1176) — an in-silico prediction, not a clinical call.

OCRL p.Met299Ile

c.897G>A · rs138260625 · VCV129851

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1176 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.11%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.1176	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.4	GERP 1.7, phastCons 0.98
Regional constraint	o/e 0.54	unconstrained · MANE · 31 kb · p 4.7e-26 · regional, not allelic
Overall
CADD	17.88	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 4.11% Admixed American · 1,882/45,760 alleles

Filtering AF 3.96% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.9%

Overall 0.163% 1,963/1,205,463 alleles · low-frequency exomes 1,630/1,093,466 · genomes 333/111,997 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	4.11%	24
Remaining individualsnot grpmax-eligible	0.099%	1,010
African / African-American	0.0367%	2,724
European (non-Finnish)	0.00146%	68,538

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.Met299Ile
Coding: c.897G>A
MANE Select: NM_000276
dbSNP: rs138260625
Type: single nucleotide variant
Location: chrX:129561251 (GRCh38)
Structure: AlphaFold pLDDT 82.91 · 5 PDB
Residue 299: the 5-ppase domain; an α-helix

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.Met299Val Uncertain significance ★ ⚠ 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-met299ile (accessed [today's date]).

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