Is ORC1 p.Arg830Cys (c.2488C>T) pathogenic?

ORC1 p.Arg830Cys (c.2488C>T) is classified Uncertain significance in ORC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-16). AlphaMissense: likely benign (0.2777); Ultra-rare (popmax 0.0117%, amr); Associated with Meier-Gorlin syndrome 1.

What condition is associated with ORC1 p.Arg830Cys (c.2488C>T)?

ORC1 p.Arg830Cys (c.2488C>T) is associated with Meier-Gorlin syndrome 1 (ClinVar).

How common is ORC1 p.Arg830Cys (c.2488C>T) in the general population?

ORC1 p.Arg830Cys (c.2488C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about ORC1 p.Arg830Cys (c.2488C>T)?

AlphaMissense predicts likely benign (score 0.2777) — an in-silico prediction, not a clinical call.

ORC1 p.Arg830Cys

c.2488C>T · rs757430297 · VCV1018780

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meier-Gorlin syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2777	likely benign
REVEL	0.4	indeterminate
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Overall
CADD	31.0	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 0.0117% Admixed American · 7/60,010 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00266% 43/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	0.00263%	38,065

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: ORC1
Protein: p.Arg830Cys
Coding: c.2488C>T
MANE Select: NM_014252 · reported on NM_004153
dbSNP: rs757430297
Type: single nucleotide variant
Location: chr1:52373279 (GRCh38)
Structure: AlphaFold pLDDT 87.43

Full ORC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meier-Gorlin syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ORC1 p.Arg105Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ORC1 p.Arg105Trp Likely pathogenic ★★ ⚠ same condition
ORC1 p.Arg321Ter Pathogenic/Likely pathogenic ★★ same condition
ORC1 p.Arg720Gln Likely pathogenic ★★ same condition
ORC1 p.Ala174Val Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala597Thr Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala857Val Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala97Ser Uncertain significance ★★ ⚠ 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/orc1-p-arg830cys (accessed [today's date]).

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