Is ABCC6 p.Glu699Asp (c.2097G>T) pathogenic?

ABCC6 p.Glu699Asp (c.2097G>T) is classified Conflicting classifications of pathogenicity in ABCC6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-02-25). AlphaMissense: likely benign (0.2036); Very rare (popmax 0.00348%, nfe); Associated with arterial calcification, generalized, of infancy, 2.

What condition is associated with ABCC6 p.Glu699Asp (c.2097G>T)?

ABCC6 p.Glu699Asp (c.2097G>T) is associated with arterial calcification, generalized, of infancy, 2, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Glu699Asp (c.2097G>T) in the general population?

ABCC6 p.Glu699Asp (c.2097G>T) is very rare (popmax 0.00348%, nfe) (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.

What do computational predictors say about ABCC6 p.Glu699Asp (c.2097G>T)?

AlphaMissense predicts likely benign (score 0.2036) — an in-silico prediction, not a clinical call.

ABCC6 p.Glu699Asp

c.2097G>T · rs72653784 · VCV433259

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arterial calcification, generalized, of infancy, 2

Computational evidence

Protein change
AlphaMissense	0.2036	likely benign
REVEL	0.717	pathogenic-leaning
SaProt	LLR -10.03	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 0.77	GERP -0.28, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	21.7	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 0.00348% European (non-Finnish) · 41/1,179,176 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.0026% 42/1,612,992 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00348%	28,760
Remaining individualsnot grpmax-eligible	0.0016%	62,434

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.Glu699Asp
Coding: c.2097G>T
MANE Select: NM_001171
dbSNP: rs72653784
Type: single nucleotide variant
Location: chr16:16182562 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 699: a UniProt-annotated variant site (in pxe; does not change protein biosynthesis and folding); the abc transporter 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: 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 p.Glu699Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC6 p.Glu699Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC6 p.Glu699Gln Uncertain significance ★ ⚠ same residue
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

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-glu699asp (accessed [today's date]).

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