Is OCRL p.Arg689Cys (c.2065C>T) pathogenic?

OCRL p.Arg689Cys (c.2065C>T) is classified Uncertain significance in OCRL (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-11). AlphaMissense: likely benign (0.2189); Very rare (popmax 0.00352%, sas).

How common is OCRL p.Arg689Cys (c.2065C>T) in the general population?

OCRL p.Arg689Cys (c.2065C>T) is very rare (popmax 0.00352%, sas) (gnomAD).

What do computational predictors say about OCRL p.Arg689Cys (c.2065C>T)?

AlphaMissense predicts likely benign (score 0.2189) — an in-silico prediction, not a clinical call.

OCRL p.Arg689Cys

c.2065C>T · rs1169836029 · VCV1306471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2189	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -10.81	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.72, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 31 kb · p 4.7e-26 · regional, not allelic
Overall
CADD	23.0	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 0.00352% South Asian · 2/56,812 alleles

Filtering AF 0.000584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000496% 6/1,209,610 alleles · very rare exomes 5/1,097,431 · genomes 1/112,179 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00352%	28,406
African / African-American	0.00175%	57,243
European (non-Finnish)	0.000335%	298,240

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.Arg689Cys
Coding: c.2065C>T
MANE Select: NM_000276
dbSNP: rs1169836029
Type: single nucleotide variant
Location: chrX:129576502 (GRCh38)
Structure: AlphaFold pLDDT 82.91 · 5 PDB
Residue 689: an α-helix

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

Similar variants

OCRL p.Arg689His Conflicting classifications of pathogenicity ★ ⚠ same residue
OCRL c.1244+1G>A Pathogenic/Likely pathogenic ★★ same type
OCRL c.1714-1G>A Pathogenic ★★ same type
OCRL c.2256+1G>T Likely pathogenic ★★ same type
OCRL c.560+1G>C Pathogenic/Likely pathogenic ★★ same type
OCRL c.940-11G>A Pathogenic/Likely pathogenic ★★ same type
OCRL p.Ala861Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
OCRL p.Arg318Cys Pathogenic/Likely pathogenic ★★ same type

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-arg689cys (accessed [today's date]).

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