Is ABCC6 p.Leu1097Ile (c.3289C>A) pathogenic?

ABCC6 p.Leu1097Ile (c.3289C>A) is classified Benign/Likely benign in ABCC6 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1039); Low-frequency (popmax 2.55%, afr); Associated with pseudoxanthoma elasticum, forme fruste.

What condition is associated with ABCC6 p.Leu1097Ile (c.3289C>A)?

ABCC6 p.Leu1097Ile (c.3289C>A) is associated with pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum, arterial calcification, generalized, of infancy, 2 (ClinVar).

How common is ABCC6 p.Leu1097Ile (c.3289C>A) in the general population?

ABCC6 p.Leu1097Ile (c.3289C>A) is low-frequency (popmax 2.55%, afr) (gnomAD).

What do computational predictors say about ABCC6 p.Leu1097Ile (c.3289C>A)?

AlphaMissense predicts likely benign (score 0.1039) — an in-silico prediction, not a clinical call.

ABCC6 p.Leu1097Ile

c.3289C>A · rs60707953 · VCV679625

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1039 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.55%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pseudoxanthoma elasticum, forme fruste

Computational evidence

Protein change
AlphaMissense	0.1039	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	17.82	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 2.55% African / African-American · 1,911/75,042 alleles

Filtering AF 2.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.41%

Overall 0.21% 3,388/1,613,216 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.55%	39
Middle Eastern	0.792%	126
Admixed American	0.435%	230
Ashkenazi Jewishnot grpmax-eligible	0.399%	251
Remaining individualsnot grpmax-eligible	0.334%	299
European (non-Finnish)	0.0698%	1,432
South Asian	0.0187%	5,358

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.Leu1097Ile
Coding: c.3289C>A
MANE Select: NM_001171
dbSNP: rs60707953
Type: single nucleotide variant
Location: chr16:16165640 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1097: a UniProt-annotated variant site (in); the abc transmembrane type-1 2 domain

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 p.Leu1097= Likely benign ★ 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-leu1097ile (accessed [today's date]).

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