Is ABCB6 p.Arg685Cys (c.2053C>T) pathogenic?

ABCB6 p.Arg685Cys (c.2053C>T) is classified Uncertain significance in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). AlphaMissense: likely benign (0.111); Rare (popmax 0.148%, afr).

How common is ABCB6 p.Arg685Cys (c.2053C>T) in the general population?

ABCB6 p.Arg685Cys (c.2053C>T) is rare (popmax 0.148%, afr) (gnomAD).

What do computational predictors say about ABCB6 p.Arg685Cys (c.2053C>T)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

ABCB6 p.Arg685Cys

c.2053C>T · rs139523052 · VCV2851475

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	33.0	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 0.148% African / African-American · 111/75,020 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.00973% 157/1,614,140 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.148%	676
Admixed American	0.045%	2,223
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.016%	6,251
South Asian	0.0011%	91,086
European (non-Finnish)	0.000508%	196,670

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.Arg685Cys
Coding: c.2053C>T
MANE Select: NM_005689
dbSNP: rs139523052
Type: single nucleotide variant
Location: chr2:219211024 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 685: an α-helix; the abc transporter domain

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

Similar variants

ABCB6 p.Arg685His 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-arg685cys (accessed [today's date]).

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