Is ABCC6 p.Arg1339Cys (c.4015C>T) pathogenic?

ABCC6 p.Arg1339Cys (c.4015C>T) is classified Pathogenic in ABCC6 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.2582); Ultra-rare (popmax 0.0168%, amr); Associated with ABCC6-related disorder.

What condition is associated with ABCC6 p.Arg1339Cys (c.4015C>T)?

ABCC6 p.Arg1339Cys (c.4015C>T) is associated with ABCC6-related disorder, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Arg1339Cys (c.4015C>T) in the general population?

ABCC6 p.Arg1339Cys (c.4015C>T) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about ABCC6 p.Arg1339Cys (c.4015C>T)?

AlphaMissense predicts likely benign (score 0.2582) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg1339Cys

c.4015C>T · rs28939702 · VCV6576

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2582 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCC6-related disorder

Computational evidence

Protein change
AlphaMissense	0.2582	likely benign ⚠ discordant with ClinVar
REVEL	0.764	pathogenic-leaning
SaProt	LLR -14.37	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 0.86	GERP -0.77
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	23.5	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 0.0168% Admixed American · 10/59,696 alleles

Filtering AF 0.00904% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00478% 77/1,611,470 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,970
South Asian	0.011%	9,052
Remaining individualsnot grpmax-eligible	0.00961%	10,401
African / African-American	0.00535%	18,706
Finnishnot grpmax-eligible	0.00471%	21,239
European (non-Finnish)	0.00365%	27,420
East Asian	0.00224%	44,738

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: ABCC6
Protein: p.Arg1339Cys
Coding: c.4015C>T
MANE Select: NM_001171
dbSNP: rs28939702
Type: single nucleotide variant
Location: chr16:16154899 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1339: a UniProt-annotated variant site (in pxe); an α-helix; the abc transporter 2 domain

Full ABCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ABCC6-related disorder

Also linked: autosomal recessive inherited pseudoxanthoma elasticum

Similar variants

ABCC6 p.Arg1339His Pathogenic/Likely pathogenic ★★ ⚠ same residue
ABCC6 p.Arg1339Leu Uncertain significance ⚠ same residue
ABCC6 p.Arg1339Ser Likely pathogenic ★ same residue
ABCC6 p.Arg1339= Likely benign ★ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.2071-1G>A Likely pathogenic ★★ same condition
ABCC6 c.2591-1G>T Likely pathogenic ★★ same condition
ABCC6 c.2787+1G>T Pathogenic ★★ 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/abcc6-p-arg1339cys (accessed [today's date]).

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