Is ABCC6 p.Arg760Trp (c.2278C>T) pathogenic?

ABCC6 p.Arg760Trp (c.2278C>T) is classified Pathogenic/Likely pathogenic in ABCC6 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.6838); Ultra-rare (popmax 0.0347%, mid); Associated with ABCC6-related disorder.

What condition is associated with ABCC6 p.Arg760Trp (c.2278C>T)?

ABCC6 p.Arg760Trp (c.2278C>T) is associated with ABCC6-related disorder, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Arg760Trp (c.2278C>T) in the general population?

ABCC6 p.Arg760Trp (c.2278C>T) is ultra-rare (popmax 0.0347%, mid) (gnomAD).

What do computational predictors say about ABCC6 p.Arg760Trp (c.2278C>T)?

AlphaMissense predicts likely pathogenic (score 0.6838) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg760Trp

c.2278C>T · rs72653788 · VCV433268

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.6838 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCC6-related disorder

Computational evidence

Protein change
AlphaMissense	0.6838	likely pathogenic ✓ concordant with ClinVar · top 10% in ABCC6
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -13.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	33.0	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 0.0347% Middle Eastern · 2/5,772 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.00769% 124/1,613,258 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0347%	2,886
European (non-Finnish)	0.00949%	10,536
African / African-American	0.00666%	15,010
Remaining individualsnot grpmax-eligible	0.0064%	15,618
South Asian	0.0011%	91,066

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.Arg760Trp
Coding: c.2278C>T
MANE Select: NM_001171
dbSNP: rs72653788
Type: single nucleotide variant
Location: chr16:16178935 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 760: a UniProt-annotated variant site (in pxe; protein level is 15-20% that of the wt proteins; maturation of glycan chains is not affected indicating normal trafficking from the endoplasmic reticulum to the cell membrane); an α-helix; the abc transporter 1 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.Arg760Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
ABCC6 p.Arg760Pro Pathogenic ★ 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
ABCC6 c.3507-1G>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-arg760trp (accessed [today's date]).

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