Is OCRL p.Val464Ala (c.1391T>C) pathogenic?

OCRL p.Val464Ala (c.1391T>C) is classified Benign/Likely benign in OCRL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.0571); Ultra-rare (popmax 0.0349%, afr); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with OCRL p.Val464Ala (c.1391T>C)?

OCRL p.Val464Ala (c.1391T>C) is associated with Nephrolithiasis/nephrocalcinosis, oculocerebrorenal syndrome (ClinVar).

How common is OCRL p.Val464Ala (c.1391T>C) in the general population?

OCRL p.Val464Ala (c.1391T>C) is ultra-rare (popmax 0.0349%, afr) (gnomAD).

What do computational predictors say about OCRL p.Val464Ala (c.1391T>C)?

AlphaMissense predicts likely benign (score 0.0571) — an in-silico prediction, not a clinical call.

OCRL p.Val464Ala

c.1391T>C · rs372398222 · VCV2427947

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0571 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0349%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.0571	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -7.76	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 0.6	GERP -2.3, phastCons 0.21
Regional constraint	o/e 0.54	unconstrained · MANE · 31 kb · p 4.7e-26 · regional, not allelic
Overall
CADD	9.146	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 0.0349% African / African-American · 20/57,239 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0193%

Overall 0.00174% 21/1,207,917 alleles · ultra-rare exomes 7/1,095,595 · genomes 14/112,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0349%	2,862
South Asian	0.00176%	56,755

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.Val464Ala
Coding: c.1391T>C
MANE Select: NM_000276
dbSNP: rs372398222
Type: single nucleotide variant
Location: chrX:129567288 (GRCh38)
Structure: AlphaFold pLDDT 82.91 · 5 PDB
Residue 464: the 5-ppase domain

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 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-val464ala (accessed [today's date]).

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