Is MAP2 p.Arg423Lys (c.1268G>A) pathogenic?

MAP2 p.Arg423Lys (c.1268G>A) is classified Benign in MAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely benign (0.0589); Common (popmax 26.1%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MAP2 p.Arg423Lys (c.1268G>A)?

AlphaMissense predicts likely benign (score 0.0589) — an in-silico prediction, not a clinical call.

MAP2 p.Arg423Lys

Q: How common is MAP2 p.Arg423Lys (c.1268G>A) in the general population?

MAP2 p.Arg423Lys (c.1268G>A) is common (popmax 26.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1268G>A · VCV4959558

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0589 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 26.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0589	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -4.50	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 0.52	GERP -4.3, phastCons 0.001
Overall
CADD	0.078	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 26.1% African / African-American · 19,557/74,862 alleles

Filtering AF 25.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 25.7%

Overall 8.38% 135,215/1,613,556 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	26.1%	4
East Asian	22.8%	4
South Asian	14.6%	7
Middle Eastern	12.7%	8
Ashkenazi Jewishnot grpmax-eligible	10.4%	10
Remaining individualsnot grpmax-eligible	9.58%	10
Finnishnot grpmax-eligible	8.35%	12
Admixed American	7.4%	14
European (non-Finnish)	6.15%	16
Amishnot grpmax-eligible	5.48%	18

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.Arg423Lys
Coding: c.1268G>A
MANE Select: NM_006838 · reported on NM_001375505
Type: single nucleotide variant
Location: chr2:209693438 (GRCh38)
Structure: AlphaFold pLDDT 86.07 · 40 PDB
Residue 423: a turn

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-arg423lys (accessed [today's date]).

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