Is AMIGO2 p.Phe340Leu (c.1018T>C) pathogenic?

AMIGO2 p.Phe340Leu (c.1018T>C) is classified Uncertain significance in AMIGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely pathogenic (0.6204); Very rare (popmax 0.00133%, afr).

How common is AMIGO2 p.Phe340Leu (c.1018T>C) in the general population?

AMIGO2 p.Phe340Leu (c.1018T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AMIGO2 p.Phe340Leu (c.1018T>C)?

AlphaMissense predicts likely pathogenic (score 0.6204) — an in-silico prediction, not a clinical call.

AMIGO2 p.Phe340Leu

c.1018T>C · rs2539901546 · VCV2280790

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6204	likely pathogenic
REVEL	0.644	pathogenic-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,565 bp · p 0.0042 · regional, not allelic
Overall
CADD	22.7	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 0.00133% African / African-American · 1/75,024 alleles

Overall 6.84e-05% 1/1,461,540 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.Phe340Leu
Coding: c.1018T>C
MANE Select: NM_001370299
dbSNP: rs2539901546
Type: single nucleotide variant
Location: chr12:47077985 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.93
Residue 340: the ig-like c2-type domain; a disulfide bond

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

Similar variants

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
AMIGO2 p.Arg261Ser 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-phe340leu (accessed [today's date]).

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