Is ABCB1 p.Arg669His (c.2006G>A) pathogenic?

ABCB1 p.Arg669His (c.2006G>A) is classified Uncertain significance in ABCB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0983); Ultra-rare (popmax 0.0854%, afr).

How common is ABCB1 p.Arg669His (c.2006G>A) in the general population?

ABCB1 p.Arg669His (c.2006G>A) is ultra-rare (popmax 0.0854%, afr) (gnomAD).

What do computational predictors say about ABCB1 p.Arg669His (c.2006G>A)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

ABCB1 p.Arg669His

c.2006G>A · rs146703713 · VCV2544625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0854%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -9.68	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 -1.7	GERP -2.4
Regional constraint	o/e 0.85	unconstrained · MANE · 96 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	5.221	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 0.0854% African / African-American · 64/74,910 alleles

Filtering AF 0.0686% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0625%

Overall 0.00768% 124/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0854%	1,170
Admixed American	0.0117%	8,570
Remaining individualsnot grpmax-eligible	0.008%	12,497
South Asian	0.00439%	22,772
European (non-Finnish)	0.00364%	27,442
East Asian	0.00223%	44,890

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: ABCB1
Protein: p.Arg669His
Coding: c.2006G>A
MANE Select: NM_001348946
dbSNP: rs146703713
Type: single nucleotide variant
Location: chr7:87544881 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.72 · 24 PDB
Residue 669: the 'disordered' region; a UniProt-annotated variant site (in)

Full ABCB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCB1 p.Arg669Leu Uncertain significance ★ ⚠ same residue
ABCB1 c.287-25G>T Benign ★★ same type
ABCB1 p.Ala1132= Benign/Likely benign ★★ same type
ABCB1 p.Gln1107Pro Benign/Likely benign ★★ same type
ABCB1 p.Glu243= Benign/Likely benign ★★ same type
ABCB1 p.Glu618= Likely benign ★★ same type
ABCB1 p.Gly412= Benign ★★ same type
ABCB1 p.Ile1145= Benign ★★ 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/abcb1-p-arg669his (accessed [today's date]).

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