Is MAGI2 p.Ala899Pro (c.2695G>C) pathogenic?

MAGI2 p.Ala899Pro (c.2695G>C) is classified Uncertain significance in MAGI2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-25). AlphaMissense: likely benign (0.0913); Very rare (popmax 0.00133%, afr); Associated with MAGI2-related disorder.

What condition is associated with MAGI2 p.Ala899Pro (c.2695G>C)?

MAGI2 p.Ala899Pro (c.2695G>C) is associated with MAGI2-related disorder, nephrotic syndrome 15 (ClinVar).

How common is MAGI2 p.Ala899Pro (c.2695G>C) in the general population?

MAGI2 p.Ala899Pro (c.2695G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MAGI2 p.Ala899Pro (c.2695G>C)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

MAGI2 p.Ala899Pro

c.2695G>C · rs988557174 · VCV2637167

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MAGI2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.65	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 5.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 376 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	24.1	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 0.00133% African / African-American · 1/74,922 alleles

Overall 6.2e-05% 1/1,612,492 alleles · very rare exomes 0/1,460,336 · genomes 1/152,156 · joint denominator

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: MAGI2
Protein: p.Ala899Pro
Coding: c.2695G>C
MANE Select: NM_012301
dbSNP: rs988557174
Type: single nucleotide variant
Location: chr7:78160175 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.10 · 5 PDB
Residue 899: the 'disordered' region

Full MAGI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MAGI2-related disorder

Also linked: nephrotic syndrome 15

Similar variants

MAGI2 p.Ala1028Val Uncertain significance ★★ ⚠ same condition
MAGI2 p.Ala1247Thr Uncertain significance ★★ ⚠ same condition
MAGI2 p.Ala1271Thr Uncertain significance ★★ ⚠ same condition
MAGI2 p.Ala1453Thr Uncertain significance ★★ ⚠ same condition
MAGI2 p.Ala620Gly Uncertain significance ★★ ⚠ same condition
MAGI2 p.Arg1370Pro Uncertain significance ★★ ⚠ same condition
MAGI2 p.Arg408Gln Uncertain significance ★★ ⚠ same condition
MAGI2 p.Arg508His 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/magi2-p-ala899pro (accessed [today's date]).

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