Is ABCC6 p.Arg64Gln (c.191G>A) pathogenic?

ABCC6 p.Arg64Gln (c.191G>A) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-01). AlphaMissense: likely benign (0.0827); Ultra-rare (popmax 0.0494%, mid); Associated with arterial calcification, generalized, of infancy, 2.

What condition is associated with ABCC6 p.Arg64Gln (c.191G>A)?

ABCC6 p.Arg64Gln (c.191G>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.Arg64Gln (c.191G>A) in the general population?

ABCC6 p.Arg64Gln (c.191G>A) is ultra-rare (popmax 0.0494%, mid) (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.Arg64Gln (c.191G>A)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg64Gln

c.191G>A · rs777566074 · VCV433504

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arterial calcification, generalized, of infancy, 2

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.38	GERP -1.6, phastCons 0.98
Regional constraint	o/e 0.95	unconstrained · MANE · 158 bp · p 0.68 · regional, not allelic
Overall
CADD	17.64	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% Middle Eastern · 3/6,078 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00285% 46/1,613,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,026
Finnishnot grpmax-eligible	0.0266%	3,766
South Asian	0.00659%	15,173
African / African-American	0.00401%	24,960
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0032%	31,233
Admixed American	0.00167%	59,968
European (non-Finnish)	0.0011%	90,746

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.Arg64Gln
Coding: c.191G>A
MANE Select: NM_001171
dbSNP: rs777566074
Type: single nucleotide variant
Location: chr16:16221677 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 64: a UniProt-annotated variant site (found in patient with putative diagnosis of pxe; uncertain significance; localization comparable to wild-type); a UniProt-annotated variant site (in)

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.Arg64Trp 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-arg64gln (accessed [today's date]).

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