Is APBB2 p.His183Arg (c.548A>G) pathogenic?

APBB2 p.His183Arg (c.548A>G) is classified Uncertain significance in APBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-10). AlphaMissense: likely benign (0.0607); Very rare (popmax 0.00195%, nfe).

How common is APBB2 p.His183Arg (c.548A>G) in the general population?

APBB2 p.His183Arg (c.548A>G) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about APBB2 p.His183Arg (c.548A>G)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

APBB2 p.His183Arg

c.548A>G · rs374154927 · VCV2212929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -5.84	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 -0.75	GERP -5.2
Regional constraint	o/e 0.79	unconstrained · MANE · 217 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	1.32	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00195% European (non-Finnish) · 23/1,180,042 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,614,070 alleles · very rare exomes 21/1,461,880 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,306
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.His183Arg
Coding: c.548A>G
MANE Select: NM_004307
dbSNP: rs374154927
Type: single nucleotide variant
Location: chr4:41013870 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 61.73
Residue 183: the 'disordered' region

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-his183arg (accessed [today's date]).

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