Is ORC6 p.Arg41Ser (c.121C>A) pathogenic?

ORC6 p.Arg41Ser (c.121C>A) is classified Uncertain significance in ORC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.2248); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ORC6 p.Arg41Ser (c.121C>A)?

ORC6 p.Arg41Ser (c.121C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ORC6 p.Arg41Ser (c.121C>A) in the general population?

ORC6 p.Arg41Ser (c.121C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ORC6 p.Arg41Ser (c.121C>A)?

AlphaMissense predicts likely benign (score 0.2248) — an in-silico prediction, not a clinical call.

ORC6 p.Arg41Ser

c.121C>A · VCV4626702

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2248 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2248	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -4.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 5.1, phastCons 0.27
Regional constraint	o/e 1.12	unconstrained · MANE · 7,876 bp · p 0.041 · regional, not allelic
Overall
CADD	18.69	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

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: ORC6
Protein: p.Arg41Ser
Coding: c.121C>A
MANE Select: NM_014321
Type: single nucleotide variant
Location: chr16:46691046 (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 41: a β-strand

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.Arg41His Likely benign ★ same residue
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

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-arg41ser (accessed [today's date]).

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