Is AMIGO3 p.Pro220Ser (c.658C>T) pathogenic?

AMIGO3 p.Pro220Ser (c.658C>T) is classified Uncertain significance in AMIGO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1923); Very rare (popmax 0.00668%, eas).

How common is AMIGO3 p.Pro220Ser (c.658C>T) in the general population?

AMIGO3 p.Pro220Ser (c.658C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about AMIGO3 p.Pro220Ser (c.658C>T)?

AlphaMissense predicts likely benign (score 0.1923) — an in-silico prediction, not a clinical call.

AMIGO3 p.Pro220Ser

c.658C>T · VCV4640225

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1923	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -8.31	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 9.9	GERP 2.8, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,511 bp · p 0.0027 · regional, not allelic
Overall
CADD	19.63	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 0.00668% East Asian · 3/44,882 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000186% 3/1,613,348 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: AMIGO3
Protein: p.Pro220Ser
Coding: c.658C>T
MANE Select: NM_198722
Type: single nucleotide variant
Location: chr3:49718808 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.90
Residue 220: the lrrct domain

Full AMIGO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMIGO3 p.Ala108Thr Uncertain significance ★ ⚠ same type
AMIGO3 p.Ala123Val Uncertain significance ★ ⚠ same type
AMIGO3 p.Ala205Gly Uncertain significance ★ ⚠ same type
AMIGO3 p.Ala333Thr Uncertain significance ★ ⚠ same type
AMIGO3 p.Ala347Thr Uncertain significance ★ ⚠ same type
AMIGO3 p.Ala41Thr Uncertain significance ★ ⚠ same type
AMIGO3 p.Ala493Ser Uncertain significance ★ ⚠ same type
AMIGO3 p.Ala493Thr 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/amigo3-p-pro220ser (accessed [today's date]).

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