Is AP2B1 p.Val43Met (c.127G>A) pathogenic?

AP2B1 p.Val43Met (c.127G>A) is classified Uncertain significance in AP2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.9895); Very rare (popmax 0.00167%, amr).

How common is AP2B1 p.Val43Met (c.127G>A) in the general population?

AP2B1 p.Val43Met (c.127G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about AP2B1 p.Val43Met (c.127G>A)?

AlphaMissense predicts likely pathogenic (score 0.9895) — an in-silico prediction, not a clinical call.

AP2B1 p.Val43Met

c.127G>A · VCV4114974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9895	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -12.85	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.18	constrained · MANE · 4,298 bp · p 5.1e-09 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/59,946 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000311% 5/1,609,412 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,946
Remaining individualsnot grpmax-eligible	0.00161%	62,228
European (non-Finnish)	0.000255%	392,235

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: AP2B1
Protein: p.Val43Met
Coding: c.127G>A
MANE Select: NM_001030006
Type: single nucleotide variant
Location: chr17:35598319 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.48 · 22 PDB
Residue 43: a turn

Full AP2B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2B1 p.Leu199= Benign ★★ same type
AP2B1 p.Ala612Thr Uncertain significance ★ ⚠ same type
AP2B1 p.Ala723Val Uncertain significance ★ ⚠ same type
AP2B1 p.Ala77Gly Uncertain significance ★ ⚠ same type
AP2B1 p.Arg746His Uncertain significance ★ ⚠ same type
AP2B1 p.Asn152Ser Uncertain significance ★ ⚠ same type
AP2B1 p.Asn179Asp Uncertain significance ★ ⚠ same type
AP2B1 p.Asn195Ser 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/ap2b1-p-val43met (accessed [today's date]).

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