Is APOB p.Arg2219Cys (c.6655C>T) pathogenic?

APOB p.Arg2219Cys (c.6655C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-04-28). AlphaMissense: likely benign (0.1031); Ultra-rare (popmax 0.0222%, nfe); Associated with hypercholesterolemia, autosomal dominant, type B.

How common is APOB p.Arg2219Cys (c.6655C>T) in the general population?

APOB p.Arg2219Cys (c.6655C>T) is ultra-rare (popmax 0.0222%, nfe) (gnomAD).

What do computational predictors say about APOB p.Arg2219Cys (c.6655C>T)?

AlphaMissense predicts likely benign (score 0.1031) — an in-silico prediction, not a clinical call.

APOB p.Arg2219Cys

Q: What condition is associated with APOB p.Arg2219Cys (c.6655C>T)?

APOB p.Arg2219Cys (c.6655C>T) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

c.6655C>T · rs141641980 · VCV402377

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1031 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
AlphaMissense	0.1031	likely benign
REVEL	0.148	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -1.7, phastCons 0.87
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	19.66	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 0.0222% European (non-Finnish) · 258/1,161,138 alleles

Filtering AF 0.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.0172% 272/1,583,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0222%	4,501
Remaining individualsnot grpmax-eligible	0.0131%	7,633
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,068
South Asian	0.00342%	29,205
East Asian	0.00226%	44,268
Admixed American	0.00172%	58,062

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: APOB
Protein: p.Arg2219Cys
Coding: c.6655C>T
MANE Select: NM_000384
dbSNP: rs141641980
Type: single nucleotide variant
Location: chr2:21010213 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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

Disease context

hypercholesterolemia, autosomal dominant, type B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypobetalipoproteinemia 1

Similar variants

APOB p.Arg2219= Likely benign ★★ same residue
APOB p.Arg2219His Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB c.1830-1G>A Pathogenic ★★ same condition
APOB c.2604+1G>A Likely pathogenic ★★ same condition
APOB c.537+1G>T Pathogenic/Likely pathogenic ★★ same condition
APOB p.Arg1333Ter Pathogenic ★★ same condition
APOB p.Arg2012Ter Pathogenic ★★ same condition
APOB p.Arg2085Ter Pathogenic/Likely pathogenic ★★ same condition

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/apob-p-arg2219cys (accessed [today's date]).

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