Is ORC4 p.Ser32fs (c.92dup) pathogenic?

ORC4 p.Ser32fs (c.92dup) is classified Pathogenic in ORC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-14). Very rare (popmax 0.00134%, afr).

How common is ORC4 p.Ser32fs (c.92dup) in the general population?

ORC4 p.Ser32fs (c.92dup) is very rare (popmax 0.00134%, afr) (gnomAD).

ORC4 p.Ser32fs

c.92dup · rs780889272 · VCV2828556

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.23	GERP 0.8, phastCons 0.97

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,836 alleles

Overall 0.000125% 2/1,606,258 alleles · very rare exomes 2/1,454,098 · genomes 0/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,836
European (non-Finnish)	8.52e-05%	1,173,730

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.Ser32fs
Coding: c.92dup
MANE Select: NM_181741
dbSNP: rs780889272
Type: Duplication
Location: chr2:147973489 (GRCh38)
Gene constraint: LOEUF 1.532 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 15 PDB

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

Similar variants

ORC4 p.Ser306fs Pathogenic/Likely pathogenic ★★ same type
ORC4 c.763-9dup Benign/Likely benign ★★ same type
ORC4 c.959-15dup Benign/Likely benign ★★ same type
ORC4 c.-17-5dup Benign ★★ same type
ORC4 p.Ala292fs Pathogenic ★ same type
ORC4 p.Leu95fs Pathogenic ★ same type
ORC4 p.Ser310Ter Pathogenic ★ same type
ORC4 p.Tyr174fs Pathogenic ★ 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-ser32fs (accessed [today's date]).

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