Is ORC4 p.Ser235Phe (c.704C>T) pathogenic?

ORC4 p.Ser235Phe (c.704C>T) is classified Uncertain significance in ORC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.1219); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ORC4 p.Ser235Phe (c.704C>T)?

ORC4 p.Ser235Phe (c.704C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ORC4 p.Ser235Phe (c.704C>T) in the general population?

ORC4 p.Ser235Phe (c.704C>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about ORC4 p.Ser235Phe (c.704C>T)?

AlphaMissense predicts likely benign (score 0.1219) — an in-silico prediction, not a clinical call.

ORC4 p.Ser235Phe

c.704C>T · rs1423220954 · VCV3206963

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1219	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 40 kb · p 0.77 · regional, not allelic
Overall
CADD	23.4	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 0.000509% European (non-Finnish) · 6/1,178,114 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,611,520 alleles · very rare exomes 5/1,459,564 · genomes 1/151,956 · 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.Ser235Phe
Coding: c.704C>T
MANE Select: NM_181741
dbSNP: rs1423220954
Type: single nucleotide variant
Location: chr2:147948109 (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

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-ser235phe (accessed [today's date]).

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