Is ORC4 p.Ser278Pro (c.832T>C) pathogenic?

ORC4 p.Ser278Pro (c.832T>C) is classified Uncertain significance in ORC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: ambiguous (0.355); Very rare (popmax 0.000514%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ORC4 p.Ser278Pro (c.832T>C)?

ORC4 p.Ser278Pro (c.832T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ORC4 p.Ser278Pro (c.832T>C) in the general population?

ORC4 p.Ser278Pro (c.832T>C) is very rare (popmax 0.000514%, nfe) (gnomAD).

What do computational predictors say about ORC4 p.Ser278Pro (c.832T>C)?

AlphaMissense predicts ambiguous (score 0.355) — an in-silico prediction, not a clinical call.

ORC4 p.Ser278Pro

c.832T>C · rs1414251905 · VCV3206964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000514%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.355	ambiguous
REVEL	0.375	indeterminate
SaProt	LLR -5.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 40 kb · p 0.77 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 0.000514% European (non-Finnish) · 6/1,167,364 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000375% 6/1,599,404 alleles · very rare exomes 5/1,447,642 · genomes 1/151,762 · joint denominator

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: ORC4
Protein: p.Ser278Pro
Coding: c.832T>C
MANE Select: NM_181741
dbSNP: rs1414251905
Type: single nucleotide variant
Location: chr2:147943453 (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 278: an α-helix

Full ORC4 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

ORC4 p.Ala375Pro Uncertain significance ★★ ⚠ same condition
ORC4 p.Arg116Lys Uncertain significance ★★ ⚠ same condition
ORC4 p.Arg148Gln Uncertain significance ★★ ⚠ same condition
ORC4 p.Arg213Gln Uncertain significance ★★ same condition
ORC4 p.Arg25His Uncertain significance ★★ same condition
ORC4 p.Asn106Ser Uncertain significance ★★ ⚠ same condition
ORC4 p.Asp301Gly Uncertain significance ★★ ⚠ same condition
ORC4 p.Cys194Ser 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/orc4-p-ser278pro (accessed [today's date]).

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