Is ORC1 p.Ala557= (c.1671C>T) pathogenic?

ORC1 p.Ala557= (c.1671C>T) is classified Conflicting classifications of pathogenicity in ORC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0831%, nfe); Associated with Meier-Gorlin syndrome 1.

What condition is associated with ORC1 p.Ala557= (c.1671C>T)?

ORC1 p.Ala557= (c.1671C>T) is associated with Meier-Gorlin syndrome 1 (ClinVar).

How common is ORC1 p.Ala557= (c.1671C>T) in the general population?

ORC1 p.Ala557= (c.1671C>T) is ultra-rare (popmax 0.0831%, nfe) (gnomAD).

ORC1 p.Ala557=

c.1671C>T · rs61756137 · VCV297581

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0831%, nfe)

Conditions

Meier-Gorlin syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.058	GERP -2.5
Overall
CADD	4.593	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0831% European (non-Finnish) · 980/1,179,876 alleles

Filtering AF 0.0787% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.077%

Overall 0.0695% 1,122/1,613,966 alleles · ultra-rare exomes 987/1,461,718 · genomes 135/152,248 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.117%	854
European (non-Finnish)grpmax	0.0831%	1,204
Remaining individualsnot grpmax-eligible	0.056%	1,786
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,700
Admixed American	0.0267%	3,751
Middle Eastern	0.0165%	6,062
African / African-American	0.00933%	10,719

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala557=
Coding: c.1671C>T
MANE Select: NM_004153
dbSNP: rs61756137
Type: single nucleotide variant
Location: chr1:52384634 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.80 · 14 PDB
Residue 557: the 'necessary and sufficient for orc complex assembly' 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-ala557 (accessed [today's date]).

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