Is ABCC6 p.Arg1138Trp (c.3412C>T) pathogenic?

ABCC6 p.Arg1138Trp (c.3412C>T) is classified Pathogenic/Likely pathogenic in ABCC6 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2862); Very rare (popmax 0.00891%, eas); Associated with ABCC6-related disorder.

What condition is associated with ABCC6 p.Arg1138Trp (c.3412C>T)?

ABCC6 p.Arg1138Trp (c.3412C>T) is associated with ABCC6-related disorder, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Arg1138Trp (c.3412C>T) in the general population?

ABCC6 p.Arg1138Trp (c.3412C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about ABCC6 p.Arg1138Trp (c.3412C>T)?

AlphaMissense predicts likely benign (score 0.2862) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg1138Trp

c.3412C>T · rs28939701 · VCV6571

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCC6-related disorder

Computational evidence

Protein change
AlphaMissense	0.2862	likely benign ⚠ discordant with ClinVar
REVEL	0.912	moderately pathogenic-leaning
SaProt	LLR -13.38	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -3.4, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	24.2	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 0.00891% East Asian · 4/44,892 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00285% 46/1,613,720 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,223
African / African-American	0.00534%	18,732
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00263%	38,065
South Asian	0.0022%	45,546
Admixed American	0.00167%	59,998
Finnishnot grpmax-eligible	0.00157%	63,696

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.Arg1138Trp
Coding: c.3412C>T
MANE Select: NM_001171
dbSNP: rs28939701
Type: single nucleotide variant
Location: chr16:16163087 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1138: a UniProt-annotated variant site (in pxe); the abc transmembrane type-1 2 domain

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

Disease context

ABCC6-related disorder

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

Similar variants

ABCC6 p.Arg1138Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
ABCC6 p.Arg1138Pro Pathogenic ★ same residue
ABCC6 p.Arg1138= Likely benign ★ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.2071-1G>A Likely pathogenic ★★ same condition
ABCC6 c.2591-1G>T Likely pathogenic ★★ same condition
ABCC6 c.2787+1G>T Pathogenic ★★ same condition
ABCC6 c.3506+1G>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-arg1138trp (accessed [today's date]).

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