Is APBB3 p.Arg199Cys (c.595C>T) pathogenic?

APBB3 p.Arg199Cys (c.595C>T) is classified Uncertain significance in APBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.3119); Ultra-rare (popmax 0.0165%, mid).

How common is APBB3 p.Arg199Cys (c.595C>T) in the general population?

APBB3 p.Arg199Cys (c.595C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about APBB3 p.Arg199Cys (c.595C>T)?

AlphaMissense predicts likely benign (score 0.3119) — an in-silico prediction, not a clinical call.

APBB3 p.Arg199Cys

c.595C>T · VCV3924987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3119	likely benign
REVEL	0.519	indeterminate
SaProt	LLR -10.74	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 3,819 bp · p 0.00036 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00109% 16/1,461,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.00668%	14,961
African / African-American	0.00133%	75,048
European (non-Finnish)	0.000932%	107,275

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.Arg199Cys
Coding: c.595C>T
MANE Select: NM_133173
Type: single nucleotide variant
Location: chr5:140562131 (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.Arg199His 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-arg199cys (accessed [today's date]).

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