Is AMIGO2 p.Arg4Gly (c.10C>G) pathogenic?

AMIGO2 p.Arg4Gly (c.10C>G) is classified Uncertain significance in AMIGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.0734); Very rare (popmax 8.56e-05%, nfe).

How common is AMIGO2 p.Arg4Gly (c.10C>G) in the general population?

AMIGO2 p.Arg4Gly (c.10C>G) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about AMIGO2 p.Arg4Gly (c.10C>G)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

AMIGO2 p.Arg4Gly

c.10C>G · VCV3535706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.63	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 2.8	GERP -2.5, phastCons 0.37
Regional constraint	o/e 0.89	unconstrained · MANE · 1,565 bp · p 0.0042 · regional, not allelic
Overall
CADD	14.78	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 8.56e-05% European (non-Finnish) · 1/1,168,618 alleles

Overall 6.93e-05% 1/1,442,990 alleles · very rare

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: AMIGO2
Protein: p.Arg4Gly
Coding: c.10C>G
MANE Select: NM_001370299
Type: single nucleotide variant
Location: chr12:47078993 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.93

Full AMIGO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMIGO2 p.Arg4His Uncertain significance ★ ⚠ same residue
AMIGO2 p.Glu494= Benign ★★ same type
AMIGO2 p.Ala300Thr Uncertain significance ★ ⚠ same type
AMIGO2 p.Ala520Val Uncertain significance ★ ⚠ same type
AMIGO2 p.Ala93Thr Uncertain significance ★ ⚠ same type
AMIGO2 p.Arg203Gly Uncertain significance ★ ⚠ same type
AMIGO2 p.Arg245Pro Uncertain significance ★ ⚠ same type
AMIGO2 p.Arg246Ser Uncertain significance ★ ⚠ 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/amigo2-p-arg4gly (accessed [today's date]).

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