Is ABCC6 p.Glu559fs (c.1674del) pathogenic?

ABCC6 p.Glu559fs (c.1674del) is classified Pathogenic/Likely pathogenic in ABCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-18). Very rare (popmax 0.00133%, afr); Associated with arterial calcification, generalized, of infancy, 2.

What condition is associated with ABCC6 p.Glu559fs (c.1674del)?

ABCC6 p.Glu559fs (c.1674del) is associated with arterial calcification, generalized, of infancy, 2, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Glu559fs (c.1674del) in the general population?

ABCC6 p.Glu559fs (c.1674del) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Generalized arterial calcification of infancy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ABCC6 p.Glu559fs

c.1674del · rs1313008538 · VCV433430

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

arterial calcification, generalized, of infancy, 2

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 13 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.018	GERP 0.64, phastCons 0.001
Overall
CADD	21.6	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 0.00133% African / African-American · 1/74,912 alleles

Overall 0.000124% 2/1,613,952 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,912
European (non-Finnish)	8.47e-05%	1,180,026

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.Glu559fs
Coding: c.1674del
MANE Select: NM_001171
dbSNP: rs1313008538
Type: Deletion
Location: chr16:16188936 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 559: the abc transmembrane type-1 1 domain

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

Disease context

arterial calcification, generalized, of infancy, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pseudoxanthoma elasticum, forme fruste autosomal recessive inherited pseudoxanthoma elasticum

For Generalized arterial calcification of infancy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

ABCC6 c.2248-2_2248-1del Pathogenic ★★ same condition
ABCC6 c.3506+2_3506+5del Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.998+2_998+3del Pathogenic/Likely pathogenic ★★ same condition
ABCC6 p.Ala667fs Pathogenic/Likely pathogenic ★★ same condition
ABCC6 p.Arg473fs Pathogenic/Likely pathogenic ★★ same condition
ABCC6 p.Asp1368fs Pathogenic ★★ same condition
ABCC6 p.Leu430fs Pathogenic/Likely pathogenic ★★ same condition
ABCC6 p.Leu775fs Likely 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-glu559fs (accessed [today's date]).

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