Is ABCC6 p.Arg489Trp (c.1465C>T) pathogenic?

ABCC6 p.Arg489Trp (c.1465C>T) is classified Conflicting classifications of pathogenicity in ABCC6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1129); Ultra-rare (popmax 0.0283%, amr); Associated with ABCC6-related disorder.

What condition is associated with ABCC6 p.Arg489Trp (c.1465C>T)?

ABCC6 p.Arg489Trp (c.1465C>T) is associated with ABCC6-related disorder, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Arg489Trp (c.1465C>T) in the general population?

ABCC6 p.Arg489Trp (c.1465C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about ABCC6 p.Arg489Trp (c.1465C>T)?

AlphaMissense predicts likely benign (score 0.1129) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg489Trp

c.1465C>T · rs754360599 · VCV433473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1129 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ABCC6-related disorder

Computational evidence

Protein change
AlphaMissense	0.1129	likely benign
REVEL	0.537	indeterminate
SaProt	LLR -9.34	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 3.8	GERP 0.46, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	26.6	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 0.0283% Admixed American · 17/60,006 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00254% 41/1,614,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,530
African / African-American	0.004%	24,975
Remaining individualsnot grpmax-eligible	0.0032%	31,245
East Asian	0.00223%	44,880
European (non-Finnish)	0.00144%	69,414
South Asian	0.0011%	91,094

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.Arg489Trp
Coding: c.1465C>T
MANE Select: NM_001171
dbSNP: rs754360599
Type: single nucleotide variant
Location: chr16:16190334 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 489: the abc transmembrane type-1 1 domain

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

Disease context

ABCC6-related disorder

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

Similar variants

ABCC6 p.Arg489Gln Uncertain significance ★ ⚠ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.2071-1G>A Likely pathogenic ★★ same condition
ABCC6 c.2591-1G>T Likely pathogenic ★★ same condition
ABCC6 c.2787+1G>T Pathogenic ★★ same condition
ABCC6 c.3506+1G>A Pathogenic/Likely 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-arg489trp (accessed [today's date]).

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