Is AP3M2 p.Pro76Ala (c.226C>G) pathogenic?

AP3M2 p.Pro76Ala (c.226C>G) is classified Uncertain significance in AP3M2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely benign (0.2703); Ultra-rare (popmax 0.0134%, eas).

How common is AP3M2 p.Pro76Ala (c.226C>G) in the general population?

AP3M2 p.Pro76Ala (c.226C>G) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about AP3M2 p.Pro76Ala (c.226C>G)?

AlphaMissense predicts likely benign (score 0.2703) — an in-silico prediction, not a clinical call.

AP3M2 p.Pro76Ala

c.226C>G · rs556026683 · VCV2278129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2703 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2703	likely benign
REVEL	0.669	pathogenic-leaning
SaProt	LLR -9.31	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 227 bp · p 0.29 · regional, not allelic
Overall
CADD	25.5	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 0.0134% East Asian · 6/44,882 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00124% 20/1,614,116 alleles · ultra-rare exomes 19/1,461,876 · genomes 1/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,480
South Asian	0.0121%	8,279
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000169%	590,005

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: AP3M2
Protein: p.Pro76Ala
Coding: c.226C>G
MANE Select: NM_006803
dbSNP: rs556026683
Type: single nucleotide variant
Location: chr8:42154913 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07

Full AP3M2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP3M2 p.Ala35Val Uncertain significance ★ ⚠ same type
AP3M2 p.Arg168Gln Uncertain significance ★ ⚠ same type
AP3M2 p.Arg246His Uncertain significance ★ ⚠ same type
AP3M2 p.Arg258Cys Uncertain significance ★ ⚠ same type
AP3M2 p.Arg283Gln Uncertain significance ★ ⚠ same type
AP3M2 p.Arg283Pro Uncertain significance ★ ⚠ same type
AP3M2 p.Arg283Trp Uncertain significance ★ ⚠ same type
AP3M2 p.Arg290Cys 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/ap3m2-p-pro76ala (accessed [today's date]).

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