Is ABCC6 p.Val1298Ile (c.3892G>A) pathogenic?

ABCC6 p.Val1298Ile (c.3892G>A) is classified Conflicting classifications of pathogenicity in ABCC6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.139); Ultra-rare (popmax 0.0612%, afr); Associated with arterial calcification, generalized, of infancy, 2.

What condition is associated with ABCC6 p.Val1298Ile (c.3892G>A)?

ABCC6 p.Val1298Ile (c.3892G>A) is associated with arterial calcification, generalized, of infancy, 2, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Val1298Ile (c.3892G>A) in the general population?

ABCC6 p.Val1298Ile (c.3892G>A) is ultra-rare (popmax 0.0612%, 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.

What do computational predictors say about ABCC6 p.Val1298Ile (c.3892G>A)?

AlphaMissense predicts likely benign (score 0.139) — an in-silico prediction, not a clinical call.

ABCC6 p.Val1298Ile

c.3892G>A · rs63751325 · VCV930520

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0612%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

arterial calcification, generalized, of infancy, 2

Computational evidence

Protein change
AlphaMissense	0.139	likely benign
REVEL	0.59	indeterminate
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	25.7	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 0.0612% African / African-American · 45/73,524 alleles

Filtering AF 0.047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.042%

Overall 0.0258% 401/1,556,550 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0612%	1,634
Remaining individualsnot grpmax-eligible	0.0315%	3,179
European (non-Finnish)	0.0286%	3,498
Middle Eastern	0.0167%	5,996
South Asian	0.00709%	14,103
East Asian	0.00241%	41,458

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.Val1298Ile
Coding: c.3892G>A
MANE Select: NM_001171
dbSNP: rs63751325
Type: single nucleotide variant
Location: chr16:16155022 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1298: a UniProt-annotated variant site (in pxe; abolishes ltc4 and nem-gs transport; does not affect plasma membrane localization; does not increase extracellular pyrophosphate levels); a β-strand; the abc transporter 2 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 p.Val1298Phe Pathogenic ★ ⚠ 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
ABCC6 c.3736-1G>A Pathogenic ★★ same condition
ABCC6 c.3883-6G>A 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-p-val1298ile (accessed [today's date]).

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