Is ORC4 p.Phe245Val (c.733T>G) pathogenic?

ORC4 p.Phe245Val (c.733T>G) is classified Uncertain significance in ORC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). AlphaMissense: likely benign (0.326); Absent from gnomAD v4.1.

How common is ORC4 p.Phe245Val (c.733T>G) in the general population?

ORC4 p.Phe245Val (c.733T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ORC4 p.Phe245Val (c.733T>G)?

AlphaMissense predicts likely benign (score 0.326) — an in-silico prediction, not a clinical call.

ORC4 p.Phe245Val

c.733T>G · rs756015637 · VCV2088901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.326 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.326	likely benign
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -12.75	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 40 kb · p 0.77 · regional, not allelic
Overall
CADD	27.4	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

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: ORC4
Protein: p.Phe245Val
Coding: c.733T>G
MANE Select: NM_181741
dbSNP: rs756015637
Type: single nucleotide variant
Location: chr2:147948080 (GRCh38)
Gene constraint: LOEUF 1.532 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 15 PDB
Residue 245: an α-helix

Full ORC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ORC4 p.Phe245Ile Uncertain significance ★ ⚠ same residue
ORC4 p.Ser208Ter Pathogenic/Likely pathogenic ★★ same type
ORC4 p.Tyr174Cys Pathogenic/Likely pathogenic ★★ same type
ORC4 p.Ala375Pro Uncertain significance ★★ ⚠ same type
ORC4 p.Arg116Lys Uncertain significance ★★ ⚠ same type
ORC4 p.Arg148Gln Uncertain significance ★★ ⚠ same type
ORC4 p.Arg213Gln Uncertain significance ★★ same type
ORC4 p.Arg25His 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/orc4-p-phe245val (accessed [today's date]).

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