Is MAP2 p.Glu1228Lys (c.3682G>A) pathogenic?

MAP2 p.Glu1228Lys (c.3682G>A) is classified Uncertain significance in MAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.0699); Very rare (popmax 0.00102%, nfe).

How common is MAP2 p.Glu1228Lys (c.3682G>A) in the general population?

MAP2 p.Glu1228Lys (c.3682G>A) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about MAP2 p.Glu1228Lys (c.3682G>A)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

MAP2 p.Glu1228Lys

c.3682G>A · VCV4549336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.67	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 5.7	GERP -0.34, phastCons 1
Overall
CADD	14.01	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 0.00102% European (non-Finnish) · 12/1,180,014 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000743% 12/1,614,110 alleles · very rare exomes 12/1,461,850 · genomes 0/152,260 · 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: MAP2
Protein: p.Glu1228Lys
Coding: c.3682G>A
MANE Select: NM_001375505
Type: single nucleotide variant
Location: chr2:209695852 (GRCh38)
Structure: AlphaFold pLDDT 86.07 · 40 PDB

Full MAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2 p.Ala1074Thr Uncertain significance ★★ ⚠ same type
MAP2 p.Ala752Ser Uncertain significance ★★ ⚠ same type
MAP2 p.Arg1715His Uncertain significance ★★ ⚠ same type
MAP2 p.Val1359Ala Uncertain significance ★★ ⚠ same type
MAP2 p.Ala414Ser Benign/Likely benign ★★ same type
MAP2 p.Asp679= Benign ★★ same type
MAP2 p.Gln1760= Benign/Likely benign ★★ same type
MAP2 p.Glu1129= Benign ★★ 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/map2-p-glu1228lys (accessed [today's date]).

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