Is ABCC6 c.219+2T>C pathogenic?

ABCC6 c.219+2T>C is classified Likely pathogenic in ABCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). Absent from gnomAD v4.1; Associated with pseudoxanthoma elasticum, forme fruste.

What condition is associated with ABCC6 c.219+2T>C?

ABCC6 c.219+2T>C is associated with pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum, arterial calcification, generalized, of infancy, 2 (ClinVar).

How common is ABCC6 c.219+2T>C in the general population?

ABCC6 c.219+2T>C is absent from gnomAD v4.1 (gnomAD).

ABCC6 c.219+2T>C

VCV3578633

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

pseudoxanthoma elasticum, forme fruste

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
REVEL	0.38	indeterminate
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.64	donor loss, 2 bp away · masked 0 · deltas
Pangolin	Δ0.30	loss · gain 0.12 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Overall
CADD	25.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCC6
Coding: c.219+2T>C
MANE Select: NM_001171
Type: single nucleotide variant
Location: chr16:16221647 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB

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

Disease context

pseudoxanthoma elasticum, forme fruste — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive inherited pseudoxanthoma elasticum arterial calcification, generalized, of infancy, 2

Similar variants

ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.2591-1G>T Likely pathogenic ★★ same condition
ABCC6 c.2787+1G>T Pathogenic ★★ same condition
ABCC6 c.3507-1G>A Pathogenic ★★ same condition
ABCC6 c.37-1G>A Pathogenic ★★ same condition
ABCC6 c.3736-1G>A Pathogenic ★★ same condition
ABCC6 c.3883-6G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.4209-2A>C Pathogenic/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-c-219-plus-2t-c (accessed [today's date]).

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