Is ORC1 p.Leu622Pro (c.1865T>C) pathogenic?

ORC1 p.Leu622Pro (c.1865T>C) is classified Pathogenic in ORC1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9923); Absent from gnomAD v4.1; Associated with Meier-Gorlin syndrome 1.

What condition is associated with ORC1 p.Leu622Pro (c.1865T>C)?

ORC1 p.Leu622Pro (c.1865T>C) is associated with Meier-Gorlin syndrome 1 (ClinVar).

How common is ORC1 p.Leu622Pro (c.1865T>C) in the general population?

ORC1 p.Leu622Pro (c.1865T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ORC1 p.Leu622Pro (c.1865T>C)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

ORC1 p.Leu622Pro

c.1865T>C · rs2147923128 · VCV1173052

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meier-Gorlin syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic ✓ concordant with ClinVar · top 6% in ORC1
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -15.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ORC1
Protein: p.Leu622Pro
Coding: c.1865T>C
MANE Select: NM_014252 · reported on NM_004153
dbSNP: rs2147923128
Type: single nucleotide variant
Location: chr1:52383568 (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.Leu622= Likely benign ★ same residue
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

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-leu622pro (accessed [today's date]).

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