Is AMIGO3 p.Arg102Cys (c.304C>T) pathogenic?

AMIGO3 p.Arg102Cys (c.304C>T) is classified Uncertain significance in AMIGO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-30). AlphaMissense: likely benign (0.1595); Ultra-rare (popmax 0.0254%, afr).

How common is AMIGO3 p.Arg102Cys (c.304C>T) in the general population?

AMIGO3 p.Arg102Cys (c.304C>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about AMIGO3 p.Arg102Cys (c.304C>T)?

AlphaMissense predicts likely benign (score 0.1595) — an in-silico prediction, not a clinical call.

AMIGO3 p.Arg102Cys

c.304C>T · VCV3535754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1595 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1595	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.89, phastCons 0.99
Regional constraint	o/e 1.11	unconstrained · MANE · 1,511 bp · p 0.0027 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,942 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00155% 25/1,613,438 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,944
East Asian	0.00223%	44,892
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000254%	393,340

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.Arg102Cys
Coding: c.304C>T
MANE Select: NM_198722
Type: single nucleotide variant
Location: chr3:49719162 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.90

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-arg102cys (accessed [today's date]).

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