Is ABCB6 p.Arg439Cys (c.1315C>T) pathogenic?

ABCB6 p.Arg439Cys (c.1315C>T) is classified Uncertain significance in ABCB6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). AlphaMissense: likely pathogenic (0.7629); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with ABCB6 p.Arg439Cys (c.1315C>T)?

ABCB6 p.Arg439Cys (c.1315C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ABCB6 p.Arg439Cys (c.1315C>T) in the general population?

ABCB6 p.Arg439Cys (c.1315C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ABCB6 p.Arg439Cys (c.1315C>T)?

AlphaMissense predicts likely pathogenic (score 0.7629) — an in-silico prediction, not a clinical call.

ABCB6 p.Arg439Cys

c.1315C>T · rs746772305 · VCV2487852

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7629	likely pathogenic
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -16.04	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 9.8	GERP 1.1, 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

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 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00173% 28/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,829
South Asiangrpmax	0.0022%	45,541
European (non-Finnish)	0.00195%	51,305

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg439Cys
Coding: c.1315C>T
MANE Select: NM_005689
dbSNP: rs746772305
Type: single nucleotide variant
Location: chr2:219214460 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 439: the abc transmembrane type-1 domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCB6 p.Arg439His Uncertain significance ★ ⚠ same residue
ABCB6 p.Ala57Thr Uncertain significance ★★ ⚠ same condition
ABCB6 p.Ala66Thr Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg450Gln Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg685His Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg688Gly Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg688His Uncertain significance ★★ ⚠ same condition
ABCB6 p.Asn545Ser Uncertain significance ★★ ⚠ same condition

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-arg439cys (accessed [today's date]).

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