Is ABCC6 p.Ile501Phe (c.1501A>T) pathogenic?

ABCC6 p.Ile501Phe (c.1501A>T) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-04). AlphaMissense: likely benign (0.3184); Very rare (popmax 0.00167%, amr); Associated with pseudoxanthoma elasticum, forme fruste.

What condition is associated with ABCC6 p.Ile501Phe (c.1501A>T)?

ABCC6 p.Ile501Phe (c.1501A>T) is associated with pseudoxanthoma elasticum, forme fruste (ClinVar).

How common is ABCC6 p.Ile501Phe (c.1501A>T) in the general population?

ABCC6 p.Ile501Phe (c.1501A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCC6 p.Ile501Phe (c.1501A>T)?

AlphaMissense predicts likely benign (score 0.3184) — an in-silico prediction, not a clinical call.

ABCC6 p.Ile501Phe

c.1501A>T · rs772952563 · VCV1333802

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pseudoxanthoma elasticum, forme fruste

Computational evidence

Protein change
AlphaMissense	0.3184	likely benign
REVEL	0.554	indeterminate
SaProt	LLR -12.00	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.037	GERP -3.1, phastCons 0.003
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	17.66	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 0.00167% Admixed American · 1/60,010 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000547% 8/1,461,880 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
South Asian	0.0011%	91,080
European (non-Finnish)	0.000508%	196,671

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.Ile501Phe
Coding: c.1501A>T
MANE Select: NM_001171
dbSNP: rs772952563
Type: single nucleotide variant
Location: chr16:16190298 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 501: the abc transmembrane type-1 1 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

Similar variants

ABCC6 p.Ile501Val 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
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-ile501phe (accessed [today's date]).

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