Is ORC6 p.Pro222Ser (c.664C>T) pathogenic?

ORC6 p.Pro222Ser (c.664C>T) is classified Uncertain significance in ORC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0792); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with ORC6 p.Pro222Ser (c.664C>T)?

ORC6 p.Pro222Ser (c.664C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ORC6 p.Pro222Ser (c.664C>T) in the general population?

ORC6 p.Pro222Ser (c.664C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ORC6 p.Pro222Ser (c.664C>T)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

ORC6 p.Pro222Ser

c.664C>T · VCV4626698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.33	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 0.57	GERP 1, phastCons 0.022
Regional constraint	o/e 1.12	unconstrained · MANE · 7,876 bp · p 0.041 · regional, not allelic
Overall
CADD	11.29	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 0.00167% Admixed American · 1/60,012 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,494 alleles · very rare exomes 17/1,461,322 · genomes 0/152,172 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.00127%	78,636

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.Pro222Ser
Coding: c.664C>T
MANE Select: NM_014321
Type: single nucleotide variant
Location: chr16:46697490 (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 222: the 'disordered' region; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ORC6 p.Ala10Ser Uncertain significance ★★ ⚠ same condition
ORC6 p.Arg8Leu Uncertain significance ★★ ⚠ same condition
ORC6 p.Leu92Pro Uncertain significance ★★ ⚠ same condition
ORC6 p.Met218Arg Uncertain significance ★★ ⚠ same condition
ORC6 p.Phe105Leu Uncertain significance ★★ ⚠ same condition
ORC6 p.Ser31Phe Uncertain significance ★★ same condition
ORC6 p.Val167Ile Uncertain significance ★★ ⚠ same condition
ORC6 p.Val186Phe 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/orc6-p-pro222ser (accessed [today's date]).

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