Is APBB3 p.Arg199His (c.596G>A) pathogenic?

APBB3 p.Arg199His (c.596G>A) is classified Uncertain significance in APBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.2022); Very rare (popmax 0.00746%, nfe).

How common is APBB3 p.Arg199His (c.596G>A) in the general population?

APBB3 p.Arg199His (c.596G>A) is very rare (popmax 0.00746%, nfe) (gnomAD).

What do computational predictors say about APBB3 p.Arg199His (c.596G>A)?

AlphaMissense predicts likely benign (score 0.2022) — an in-silico prediction, not a clinical call.

APBB3 p.Arg199His

c.596G>A · rs140070711 · VCV2205228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2022 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2022	likely benign
REVEL	0.474	indeterminate
SaProt	LLR -10.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 3,819 bp · p 0.00036 · regional, not allelic
Overall
CADD	31.0	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 0.00746% European (non-Finnish) · 88/1,180,016 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00582% 94/1,614,072 alleles · very rare exomes 89/1,461,856 · genomes 5/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00746%	13,409
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0022%	45,544

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: APBB3
Protein: p.Arg199His
Coding: c.596G>A
MANE Select: NM_133173
dbSNP: rs140070711
Type: single nucleotide variant
Location: chr5:140562130 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.76 · 2 PDB
Residue 199: the pid 1 domain

Full APBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB3 p.Arg199Cys Uncertain significance ★ ⚠ same residue
APBB3 p.Ala135Gly Uncertain significance ★ ⚠ same type
APBB3 p.Ala151Val Uncertain significance ★ ⚠ same type
APBB3 p.Ala163Thr Uncertain significance ★ ⚠ same type
APBB3 p.Ala288Thr Uncertain significance ★ ⚠ same type
APBB3 p.Ala313Val Uncertain significance ★ ⚠ same type
APBB3 p.Ala475Asp Uncertain significance ★ ⚠ same type
APBB3 p.Arg122Cys 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/apbb3-p-arg199his (accessed [today's date]).

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