Is ORC3 p.Val12Ala (c.35T>C) pathogenic?

ORC3 p.Val12Ala (c.35T>C) is classified Uncertain significance in ORC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.3619); No allele count reported in gnomAD v4.1 (AN 1,585,874).

How common is ORC3 p.Val12Ala (c.35T>C) in the general population?

ORC3 p.Val12Ala (c.35T>C) is no allele count reported in gnomAD v4.1 (AN 1,585,874) (gnomAD).

What do computational predictors say about ORC3 p.Val12Ala (c.35T>C)?

AlphaMissense predicts ambiguous (score 0.3619) — an in-silico prediction, not a clinical call.

ORC3 p.Val12Ala

c.35T>C · VCV4128877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3619 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,585,874)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3619	ambiguous
REVEL	0.175	moderately benign-leaning
SaProt	LLR -6.69	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 31 kb · p 0.38 · regional, not allelic
Overall
CADD	24.4	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

No allele count reported in gnomAD v4.1 (AN 1,585,874). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ORC3
Protein: p.Val12Ala
Coding: c.35T>C
MANE Select: NM_012381
Type: single nucleotide variant
Location: chr6:87594363 (GRCh38)
Gene constraint: LOEUF 1.259 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.51 · 15 PDB
Residue 12: a β-strand

Full ORC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ORC3 p.Val12Phe Uncertain significance ★ ⚠ same residue
ORC3 p.Ala103Val Uncertain significance ★ same type
ORC3 p.Ala586Gly Uncertain significance ★ ⚠ same type
ORC3 p.Ala594Val Uncertain significance ★ ⚠ same type
ORC3 p.Arg204Ser Uncertain significance ★ ⚠ same type
ORC3 p.Arg353Gly Uncertain significance ★ ⚠ same type
ORC3 p.Arg367Gln Uncertain significance ★ ⚠ same type
ORC3 p.Arg368His Uncertain significance ★ ⚠ same type

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/orc3-p-val12ala (accessed [today's date]).

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