Is ABCB6 p.Arg723Trp (c.2167C>T) pathogenic?

ABCB6 p.Arg723Trp (c.2167C>T) is classified Uncertain significance in ABCB6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-04). AlphaMissense: likely pathogenic (0.8926); Ultra-rare (popmax 0.0669%, eas).

How common is ABCB6 p.Arg723Trp (c.2167C>T) in the general population?

ABCB6 p.Arg723Trp (c.2167C>T) is ultra-rare (popmax 0.0669%, eas) (gnomAD).

What do computational predictors say about ABCB6 p.Arg723Trp (c.2167C>T)?

AlphaMissense predicts likely pathogenic (score 0.8926) — an in-silico prediction, not a clinical call.

ABCB6 p.Arg723Trp

c.2167C>T · rs199515171 · VCV1981126

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8926 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0669%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8926	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -14.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.16, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0669% East Asian · 30/44,872 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00347% 56/1,613,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0669%	1,496
Admixed American	0.015%	6,666
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,249
African / African-American	0.00133%	75,012
European (non-Finnish)	0.0011%	90,769

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.Arg723Trp
Coding: c.2167C>T
MANE Select: NM_005689
dbSNP: rs199515171
Type: single nucleotide variant
Location: chr2:219210800 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 723: an α-helix; the abc transporter domain; a UniProt-annotated variant site (in pshk2)

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

Similar variants

ABCB6 p.Arg723Gln Uncertain significance ★★ ⚠ same residue
ABCB6 p.Ala164Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala57Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala66Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala681Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg135Ser Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg439Cys Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg450Gln 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-arg723trp (accessed [today's date]).

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