Is ABCC6 p.Arg964Pro (c.2891G>C) pathogenic?

ABCC6 p.Arg964Pro (c.2891G>C) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-06-25). AlphaMissense: ambiguous (0.4852); Very rare (popmax 0.00255%, nfe); Associated with arterial calcification, generalized, of infancy, 2.

What condition is associated with ABCC6 p.Arg964Pro (c.2891G>C)?

ABCC6 p.Arg964Pro (c.2891G>C) is associated with arterial calcification, generalized, of infancy, 2, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Arg964Pro (c.2891G>C) in the general population?

ABCC6 p.Arg964Pro (c.2891G>C) is very rare (popmax 0.00255%, nfe) (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.Arg964Pro (c.2891G>C)?

AlphaMissense predicts ambiguous (score 0.4852) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg964Pro

c.2891G>C · rs72657691 · VCV433298

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4852 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00255%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

arterial calcification, generalized, of infancy, 2

Computational evidence

Protein change
AlphaMissense	0.4852	ambiguous
REVEL	0.689	pathogenic-leaning
SaProt	LLR -6.87	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -3.4, phastCons 0.01
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	19.7	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 0.00255% European (non-Finnish) · 30/1,176,396 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00193% 31/1,605,088 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00255%	39,213
Remaining individualsnot grpmax-eligible	0.00161%	62,126

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.Arg964Pro
Coding: c.2891G>C
MANE Select: NM_001171
dbSNP: rs72657691
Type: single nucleotide variant
Location: chr16:16169750 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 964: the abc transmembrane type-1 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.Arg964Trp Uncertain significance ★ ⚠ same residue
ABCC6 p.Arg964Gln 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

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-arg964pro (accessed [today's date]).

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