Is ABCB6 p.Arg375fs (c.1123del) pathogenic?

ABCB6 p.Arg375fs (c.1123del) is classified Uncertain significance in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). Very rare (popmax 8.54e-05%, nfe).

How common is ABCB6 p.Arg375fs (c.1123del) in the general population?

ABCB6 p.Arg375fs (c.1123del) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

ABCB6 p.Arg375fs

c.1123del · rs1559237724 · VCV1952159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.54e-05% European (non-Finnish) · 1/1,171,118 alleles

Overall 6.91e-05% 1/1,446,874 alleles · very rare

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: ABCB6
Protein: p.Arg375fs
Coding: c.1123del
MANE Select: NM_005689
dbSNP: rs1559237724
Type: Deletion
Location: chr2:219216028 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 375: the abc transmembrane type-1 domain; a UniProt-annotated variant site (in pshk2); an α-helix

Full ABCB6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCB6 p.Arg375Trp Conflicting classifications of pathogenicity ★ same residue
ABCB6 p.Arg375Gln Pathogenic same residue
ABCB6 p.Trp154fs Uncertain significance ★★ same type
ABCB6 p.Asp641del Uncertain significance ★ same type
ABCB6 p.Gly318fs Uncertain significance ★ same type
ABCB6 p.Gly579fs Uncertain significance ★ same type
ABCB6 p.Val126fs Conflicting classifications of pathogenicity ★ same type
ABCB6 p.Val127del 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/abcb6-p-arg375fs (accessed [today's date]).

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