Is ORC1 p.Ser440Pro (c.1318T>C) pathogenic?

ORC1 p.Ser440Pro (c.1318T>C) is classified Conflicting classifications of pathogenicity in ORC1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.0718); Low-frequency (popmax 2.45%, mid); Associated with Meier-Gorlin syndrome 1.

What condition is associated with ORC1 p.Ser440Pro (c.1318T>C)?

ORC1 p.Ser440Pro (c.1318T>C) is associated with Meier-Gorlin syndrome 1 (ClinVar).

How common is ORC1 p.Ser440Pro (c.1318T>C) in the general population?

ORC1 p.Ser440Pro (c.1318T>C) is low-frequency (popmax 2.45%, mid) (gnomAD).

What do computational predictors say about ORC1 p.Ser440Pro (c.1318T>C)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

ORC1 p.Ser440Pro

c.1318T>C · rs61756136 · VCV211798

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.45%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meier-Gorlin syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -7.00	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 1.1	GERP 0.94, phastCons 0.076
Regional constraint	o/e 0.91	unconstrained · MANE · 29 kb · p 0.0044 · regional, not allelic
Overall
CADD	11.29	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 2.45% Middle Eastern · 148/6,052 alleles

Filtering AF 2.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 2%

Overall 0.078% 1,259/1,614,188 alleles · low-frequency exomes 1,147/1,461,858 · genomes 112/152,330 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.45%	41
Ashkenazi Jewishnot grpmax-eligible	1.12%	89
Remaining individualsnot grpmax-eligible	0.202%	496
Admixed American	0.0866%	1,154
African / African-American	0.052%	1,925
South Asian	0.0494%	2,024
European (non-Finnish)	0.0439%	2,278

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.Ser440Pro
Coding: c.1318T>C
MANE Select: NM_004153
dbSNP: rs61756136
Type: single nucleotide variant
Location: chr1:52388507 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.80 · 14 PDB
Residue 440: the 'disordered' region

Full ORC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meier-Gorlin syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ORC1 p.Arg105Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ORC1 p.Arg105Trp Likely pathogenic ★★ ⚠ same condition
ORC1 p.Arg321Ter Pathogenic/Likely pathogenic ★★ same condition
ORC1 p.Arg720Gln Likely pathogenic ★★ same condition
ORC1 p.Ala174Val Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala597Thr Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala857Val Uncertain significance ★★ ⚠ same condition
ORC1 p.Ala97Ser 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-ser440pro (accessed [today's date]).

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