Is ORC6 p.Val186Phe (c.556G>T) pathogenic?

ORC6 p.Val186Phe (c.556G>T) is classified Uncertain significance in ORC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-29). AlphaMissense: likely benign (0.0867); Ultra-rare (popmax 0.0113%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ORC6 p.Val186Phe (c.556G>T)?

ORC6 p.Val186Phe (c.556G>T) is associated with Inborn genetic diseases, Meier-Gorlin syndrome 3 (ClinVar).

How common is ORC6 p.Val186Phe (c.556G>T) in the general population?

ORC6 p.Val186Phe (c.556G>T) is ultra-rare (popmax 0.0113%, nfe) (gnomAD).

What do computational predictors say about ORC6 p.Val186Phe (c.556G>T)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

ORC6 p.Val186Phe

c.556G>T · rs368692007 · VCV319304

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.011	GERP -4.3
Regional constraint	o/e 1.12	unconstrained · MANE · 7,876 bp · p 0.041 · regional, not allelic
Overall
CADD	11.99	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 0.0113% European (non-Finnish) · 131/1,157,108 alleles

Filtering AF 0.00971% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00914%

Overall 0.00869% 138/1,588,816 alleles · ultra-rare exomes 128/1,436,600 · genomes 10/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0113%	8,833
Admixed American	0.005%	19,986
Remaining individualsnot grpmax-eligible	0.00324%	30,837
African / African-American	0.00269%	37,216

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: ORC6
Protein: p.Val186Phe
Coding: c.556G>T
MANE Select: NM_014321
dbSNP: rs368692007
Type: single nucleotide variant
Location: chr16:46695668 (GRCh38)
Gene constraint: LOEUF 1.784 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.69 · 4 PDB

Full ORC6 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

Also linked: Meier-Gorlin syndrome 3

Similar variants

ORC6 p.Val186= Likely benign ★ same residue
ORC6 p.Ala10Ser Uncertain significance ★★ ⚠ same condition
ORC6 p.Arg8Leu Uncertain significance ★★ ⚠ same condition
ORC6 p.Gln130His Uncertain significance ★★ ⚠ same condition
ORC6 p.Ile69Met Uncertain significance ★★ ⚠ same condition
ORC6 p.Leu228Val Uncertain significance ★★ ⚠ same condition
ORC6 p.Leu92Pro Uncertain significance ★★ ⚠ same condition
ORC6 p.Met218Arg 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/orc6-p-val186phe (accessed [today's date]).

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