Is ABCC6 p.Arg64Trp (c.190C>T) pathogenic?

ABCC6 p.Arg64Trp (c.190C>T) is classified Uncertain significance in ABCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-22). AlphaMissense: likely benign (0.1396); Very rare (popmax 0.00769%, sas); Associated with pseudoxanthoma elasticum, forme fruste.

What condition is associated with ABCC6 p.Arg64Trp (c.190C>T)?

ABCC6 p.Arg64Trp (c.190C>T) is associated with pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum, arterial calcification, generalized, of infancy, 2 (ClinVar).

How common is ABCC6 p.Arg64Trp (c.190C>T) in the general population?

ABCC6 p.Arg64Trp (c.190C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about ABCC6 p.Arg64Trp (c.190C>T)?

AlphaMissense predicts likely benign (score 0.1396) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg64Trp

c.190C>T · VCV3578636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pseudoxanthoma elasticum, forme fruste

Computational evidence

Protein change
AlphaMissense	0.1396	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -10.28	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 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 158 bp · p 0.68 · regional, not allelic
Overall
CADD	29.8	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 0.00769% South Asian · 7/91,064 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00291% 47/1,613,822 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0777%	1,287
South Asiangrpmax	0.00769%	13,009
Remaining individualsnot grpmax-eligible	0.0064%	15,618
East Asian	0.00223%	44,894
Finnishnot grpmax-eligible	0.00156%	64,044
European (non-Finnish)	0.000932%	107,260

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg64Trp
Coding: c.190C>T
MANE Select: NM_001171
Type: single nucleotide variant
Location: chr16:16221678 (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

pseudoxanthoma elasticum, forme fruste — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

ABCC6 p.Arg64Gln 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-arg64trp (accessed [today's date]).

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