Is ORC1 p.Pro274Ser (c.820C>T) pathogenic?

ORC1 p.Pro274Ser (c.820C>T) is classified Uncertain significance in ORC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely benign (0.0798); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with ORC1 p.Pro274Ser (c.820C>T)?

ORC1 p.Pro274Ser (c.820C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ORC1 p.Pro274Ser (c.820C>T) in the general population?

ORC1 p.Pro274Ser (c.820C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ORC1 p.Pro274Ser (c.820C>T)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

ORC1 p.Pro274Ser

c.820C>T · VCV4128846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -6.28	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 5.7	GERP 0.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 29 kb · p 0.0044 · regional, not allelic
Overall
CADD	20.5	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 0.00267% African / African-American · 2/74,890 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,924 alleles · very rare exomes 3/1,461,766 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,445
Admixed American	0.00167%	59,978
European (non-Finnish)	8.47e-05%	1,179,988

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: ORC1
Protein: p.Pro274Ser
Coding: c.820C>T
MANE Select: NM_004153
Type: single nucleotide variant
Location: chr1:52393705 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.80 · 14 PDB
Residue 274: the 'disordered' region

Full ORC1 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

ORC1 c.721+1G>C Likely pathogenic ★★ same condition
ORC1 p.Ala174Val Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala205Gly Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala597Thr Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala645Thr Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala857Val Uncertain significance ★★ ⚠ same condition
ORC1 p.Arg100Trp Uncertain significance ★★ ⚠ same condition
ORC1 p.Arg134Trp 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/orc1-p-pro274ser (accessed [today's date]).

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