Is AP2M1 p.Ala395= (c.1185G>A) pathogenic?

AP2M1 p.Ala395= (c.1185G>A) is classified Benign in AP2M1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 16.6%, sas) — too common for a highly-penetrant pathogenic allele; Associated with intellectual developmental disorder 60 with seizures.

What condition is associated with AP2M1 p.Ala395= (c.1185G>A)?

AP2M1 p.Ala395= (c.1185G>A) is associated with intellectual developmental disorder 60 with seizures (ClinVar).

AP2M1 p.Ala395=

Q: How common is AP2M1 p.Ala395= (c.1185G>A) in the general population?

AP2M1 p.Ala395= (c.1185G>A) is common (popmax 16.6%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1185G>A · rs2231224 · VCV1192406

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 16.6%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual developmental disorder 60 with seizures

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.4
Overall
CADD	8.082	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.6% South Asian · 15,125/91,080 alleles

Filtering AF 16.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.4%

Overall 14.8% 239,018/1,613,974 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	16.6%	6
European (non-Finnish)	16.5%	6
Middle Eastern	15.1%	7
Amishnot grpmax-eligible	13.7%	7
Remaining individualsnot grpmax-eligible	13.5%	7
Finnishnot grpmax-eligible	13.4%	7
Ashkenazi Jewishnot grpmax-eligible	10.6%	9
Admixed American	8.26%	12
African / African-American	3.74%	27
East Asian	0.212%	472

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: AP2M1
Protein: p.Ala395=
Coding: c.1185G>A
MANE Select: NM_004068
dbSNP: rs2231224
Type: single nucleotide variant
Location: chr3:184183493 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 3 PDB
Residue 395: the mhd domain

Full AP2M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder 60 with seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP2M1 p.Arg170Trp Pathogenic/Likely pathogenic ★★ same condition
AP2M1 p.Arg199Gln Uncertain significance ★★ ⚠ same condition
AP2M1 c.1173+73T>C Benign ★★ same condition
AP2M1 c.565+17G>A Benign ★★ same condition
AP2M1 c.75-4T>C Benign ★★ same condition
AP2M1 p.Ile320= Benign ★★ same condition
AP2M1 p.Tyr431= Benign/Likely benign ★★ same condition
AP2M1 p.Arg33Trp 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/ap2m1-p-ala395 (accessed [today's date]).

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