Is MAGI2 p.Glu1237Lys (c.3709G>A) pathogenic?

MAGI2 p.Glu1237Lys (c.3709G>A) is classified Uncertain significance in MAGI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1755); Very rare (popmax 0.00172%, amr).

How common is MAGI2 p.Glu1237Lys (c.3709G>A) in the general population?

MAGI2 p.Glu1237Lys (c.3709G>A) is very rare (popmax 0.00172%, amr) (gnomAD).

What do computational predictors say about MAGI2 p.Glu1237Lys (c.3709G>A)?

AlphaMissense predicts likely benign (score 0.1755) — an in-silico prediction, not a clinical call.

MAGI2 p.Glu1237Lys

c.3709G>A · VCV4834695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00172%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1755	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 657 bp · p 0.0014 · regional, not allelic
Overall
CADD	31.0	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 0.00172% Admixed American · 1/58,216 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00025% 4/1,602,014 alleles · very rare exomes 4/1,449,774 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00172%	58,216
South Asian	0.00112%	89,486
European (non-Finnish)	0.00017%	587,976

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.Glu1237Lys
Coding: c.3709G>A
MANE Select: NM_012301
Type: single nucleotide variant
Location: chr7:78019974 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.10 · 5 PDB
Residue 1237: the 'disordered' region

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

Similar variants

MAGI2 p.Glu1237Ter Uncertain significance ★ same residue
MAGI2 p.Ala1028Val Uncertain significance ★★ ⚠ same type
MAGI2 p.Ala1247Thr Uncertain significance ★★ ⚠ same type
MAGI2 p.Ala1271Thr Uncertain significance ★★ ⚠ same type
MAGI2 p.Ala1453Thr Uncertain significance ★★ ⚠ same type
MAGI2 p.Ala274Thr Uncertain significance ★★ ⚠ same type
MAGI2 p.Ala620Gly Uncertain significance ★★ ⚠ same type
MAGI2 p.Ala809Ser 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/magi2-p-glu1237lys (accessed [today's date]).

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