Is ABCC6 p.Glu709Lys (c.2125G>A) pathogenic?

ABCC6 p.Glu709Lys (c.2125G>A) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-09). AlphaMissense: likely benign (0.1066); Ultra-rare (popmax 0.0334%, eas); Associated with autosomal recessive inherited pseudoxanthoma elasticum.

What condition is associated with ABCC6 p.Glu709Lys (c.2125G>A)?

ABCC6 p.Glu709Lys (c.2125G>A) is associated with autosomal recessive inherited pseudoxanthoma elasticum, pseudoxanthoma elasticum, forme fruste, arterial calcification, generalized, of infancy, 2 (ClinVar).

How common is ABCC6 p.Glu709Lys (c.2125G>A) in the general population?

ABCC6 p.Glu709Lys (c.2125G>A) is ultra-rare (popmax 0.0334%, eas) (gnomAD).

How is Pseudoxanthoma elasticum inherited?

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

What do computational predictors say about ABCC6 p.Glu709Lys (c.2125G>A)?

AlphaMissense predicts likely benign (score 0.1066) — an in-silico prediction, not a clinical call.

ABCC6 p.Glu709Lys

c.2125G>A · rs114303883 · VCV433460

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1066 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive inherited pseudoxanthoma elasticum

Computational evidence

Protein change
AlphaMissense	0.1066	likely benign
REVEL	0.686	pathogenic-leaning
SaProt	LLR -11.00	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.34	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 0.83, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	24.3	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 0.0334% East Asian · 15/44,884 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.00279% 45/1,614,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0334%	2,992
Remaining individualsnot grpmax-eligible	0.032%	3,124
African / African-American	0.00534%	18,734
European (non-Finnish)	0.000508%	196,672

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.Glu709Lys
Coding: c.2125G>A
MANE Select: NM_001171
dbSNP: rs114303883
Type: single nucleotide variant
Location: chr16:16182534 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 709: a UniProt-annotated variant site (found in patient with putative diagnosis of pex; uncertain significance; loss-of-function mutation; localization comparable to wild-type); an α-helix; the abc transporter 1 domain

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

Disease context

autosomal recessive inherited pseudoxanthoma elasticum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pseudoxanthoma elasticum, forme fruste arterial calcification, generalized, of infancy, 2

For Pseudoxanthoma elasticum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ABCC6 p.Glu709Ter Pathogenic ★ same residue
ABCC6 p.Glu709Gly Uncertain significance ⚠ same residue
ABCC6 p.Glu709Gln 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-glu709lys (accessed [today's date]).

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