Is ABCB6 p.Val126fs (c.376del) pathogenic?

ABCB6 p.Val126fs (c.376del) is classified Conflicting classifications of pathogenicity in ABCB6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-28). Rare (popmax 0.132%, afr).

How common is ABCB6 p.Val126fs (c.376del) in the general population?

ABCB6 p.Val126fs (c.376del) is rare (popmax 0.132%, afr) (gnomAD).

ABCB6 p.Val126fs

c.376del · rs377591749 · VCV2862558

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.132%, afr)

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 1 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.9	GERP 0.15, phastCons 0.89
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% African / African-American · 99/75,066 alleles

Filtering AF 0.111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.00701% 113/1,613,106 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.132%	758
Remaining individualsnot grpmax-eligible	0.016%	6,249
Admixed American	0.00666%	15,007

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.Val126fs
Coding: c.376del
MANE Select: NM_005689
dbSNP: rs377591749
Type: Deletion
Location: chr2:219218298 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 126: the 'required for atpase activity' region; the 'required for the lysosomal targeting' region

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

Similar variants

ABCB6 p.Trp154fs Uncertain significance ★★ same type
ABCB6 p.Arg375fs 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.Val127del Uncertain significance ★ same type
ABCB6 p.Val265fs Uncertain significance ★ same type
ABCB6 c.687+26del 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/abcb6-p-val126fs (accessed [today's date]).

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