Is APBB2 p.Glu643Lys (c.1927G>A) pathogenic?

APBB2 p.Glu643Lys (c.1927G>A) is classified Uncertain significance in APBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.0941); Rare (popmax 0.115%, mid).

How common is APBB2 p.Glu643Lys (c.1927G>A) in the general population?

APBB2 p.Glu643Lys (c.1927G>A) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about APBB2 p.Glu643Lys (c.1927G>A)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

APBB2 p.Glu643Lys

c.1927G>A · rs756658820 · VCV3127692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -10.69	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 217 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E642K vs ClinVar E643K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,080 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00647% 104/1,608,286 alleles · rare exomes 99/1,456,066 · genomes 5/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Admixed American	0.0467%	2,143
Remaining individualsnot grpmax-eligible	0.0273%	3,667
African / African-American	0.00401%	24,939
European (non-Finnish)	0.004%	25,000
South Asian	0.0022%	45,491

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: APBB2
Protein: p.Glu643Lys
Coding: c.1927G>A
MANE Select: NM_004307
dbSNP: rs756658820
Type: single nucleotide variant
Location: chr4:40823649 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 61.73
Residue 642 UniProt numbering: the pid 2 domain

Full APBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB2 c.20-6C>T Benign ★★ same type
APBB2 p.Ala111Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala126Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala197Val Uncertain significance ★ ⚠ same type
APBB2 p.Ala224Asp Uncertain significance ★ ⚠ same type
APBB2 p.Ala279Val Uncertain significance ★ same type
APBB2 p.Ala436Pro Uncertain significance ★ ⚠ same type
APBB2 p.Ala436Thr 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/apbb2-p-glu643lys (accessed [today's date]).

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