Is ABCC6 p.Arg899Cys (c.2695C>T) pathogenic?

ABCC6 p.Arg899Cys (c.2695C>T) is classified Likely benign in ABCC6 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0879); Rare (popmax 0.408%, afr); Associated with autosomal recessive inherited pseudoxanthoma elasticum.

What condition is associated with ABCC6 p.Arg899Cys (c.2695C>T)?

ABCC6 p.Arg899Cys (c.2695C>T) is associated with autosomal recessive inherited pseudoxanthoma elasticum, pseudoxanthoma elasticum, forme fruste, arterial calcification, generalized, of infancy, 2 (ClinVar).

How common is ABCC6 p.Arg899Cys (c.2695C>T) in the general population?

ABCC6 p.Arg899Cys (c.2695C>T) is rare (popmax 0.408%, afr) (gnomAD).

How is Pseudoxanthoma elasticum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCC6 p.Arg899Cys (c.2695C>T)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg899Cys

c.2695C>T · rs11861980 · VCV710346

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.408%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive inherited pseudoxanthoma elasticum

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5	GERP -1.1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	10.81	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 0.408% African / African-American · 306/75,004 alleles

Filtering AF 0.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.356%

Overall 0.022% 355/1,614,060 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.408%	245
Admixed American	0.035%	2,857
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0304%	3,290
East Asian	0.00223%	44,872
South Asian	0.0022%	45,539
European (non-Finnish)	0.000339%	295,004

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.Arg899Cys
Coding: c.2695C>T
MANE Select: NM_001171
dbSNP: rs11861980
Type: single nucleotide variant
Location: chr16:16173376 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 899: the 'disordered' region

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

Disease context

autosomal recessive inherited pseudoxanthoma elasticum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Pseudoxanthoma elasticum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ABCC6 p.Arg899His Likely benign ★★ same residue
ABCC6 p.Arg899Ser 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-arg899cys (accessed [today's date]).

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