Is ORC6 p.Pro11Arg (c.32C>G) pathogenic?

ORC6 p.Pro11Arg (c.32C>G) is classified Uncertain significance in ORC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-18). AlphaMissense: likely benign (0.0823); Very rare (popmax 0.00511%, amr); Associated with Meier-Gorlin syndrome 3.

What condition is associated with ORC6 p.Pro11Arg (c.32C>G)?

ORC6 p.Pro11Arg (c.32C>G) is associated with Meier-Gorlin syndrome 3 (ClinVar).

How common is ORC6 p.Pro11Arg (c.32C>G) in the general population?

ORC6 p.Pro11Arg (c.32C>G) is very rare (popmax 0.00511%, amr) (gnomAD).

What do computational predictors say about ORC6 p.Pro11Arg (c.32C>G)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

ORC6 p.Pro11Arg

c.32C>G · rs757562073 · VCV887921

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00511%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meier-Gorlin syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -4.70	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 -0.81	GERP 1.2
Regional constraint	o/e 1.12	unconstrained · MANE · 7,876 bp · p 0.041 · regional, not allelic
Overall
CADD	2.363	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00511% Admixed American · 3/58,670 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000676%

Overall 0.000624% 10/1,601,936 alleles · very rare exomes 8/1,449,726 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00511%	19,557
African / African-American	0.00401%	24,947
East Asian	0.00225%	44,512
European (non-Finnish)	0.000255%	391,564

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: ORC6
Protein: p.Pro11Arg
Coding: c.32C>G
MANE Select: NM_014321
dbSNP: rs757562073
Type: single nucleotide variant
Location: chr16:46689737 (GRCh38)
Gene constraint: LOEUF 1.784 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.69 · 4 PDB
Residue 11: an α-helix

Full ORC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meier-Gorlin syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ORC6 p.Arg8Leu Uncertain significance ★★ ⚠ same condition
ORC6 p.Gln130His Uncertain significance ★★ ⚠ same condition
ORC6 p.Ile69Met Uncertain significance ★★ ⚠ same condition
ORC6 p.Leu228Val Uncertain significance ★★ ⚠ same condition
ORC6 p.Pro138Gln Uncertain significance ★★ ⚠ same condition
ORC6 p.Val186Phe Uncertain significance ★★ ⚠ same condition
ORC6 c.-20T>C Benign ★★ same condition
ORC6 c.-47G>A Benign/Likely benign ★★ 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/orc6-p-pro11arg (accessed [today's date]).

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