Is ABCC6 p.Arg765Gln (c.2294G>A) pathogenic?

ABCC6 p.Arg765Gln (c.2294G>A) is classified Pathogenic in ABCC6 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.2306); Very rare (popmax 0.00659%, sas); Associated with Autosomal recessive ABCC6-related disorders.

What condition is associated with ABCC6 p.Arg765Gln (c.2294G>A)?

ABCC6 p.Arg765Gln (c.2294G>A) is associated with Autosomal recessive ABCC6-related disorders, pseudoxanthoma elasticum, forme fruste, autosomal recessive inherited pseudoxanthoma elasticum (ClinVar).

How common is ABCC6 p.Arg765Gln (c.2294G>A) in the general population?

ABCC6 p.Arg765Gln (c.2294G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about ABCC6 p.Arg765Gln (c.2294G>A)?

AlphaMissense predicts likely benign (score 0.2306) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg765Gln

c.2294G>A · rs67561842 · VCV30337

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Autosomal recessive ABCC6-related disorders

Computational evidence

Protein change
AlphaMissense	0.2306	likely benign ⚠ discordant with ClinVar
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -12.80	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 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	28.2	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 0.00659% South Asian · 6/91,078 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.0026% 42/1,613,428 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,180
Admixed American	0.005%	20,000
European (non-Finnish)	0.00263%	38,065
East Asian	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Arg765Gln
Coding: c.2294G>A
MANE Select: NM_001171
dbSNP: rs67561842
Type: single nucleotide variant
Location: chr16:16178919 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 765: a UniProt-annotated variant site (in pxe; affects protein expression and trafficking; expression is reduced to less than 10%, when compared with the wt protein); an α-helix; the abc transporter 1 domain

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

Disease context

Autosomal recessive ABCC6-related disorders

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

Similar variants

ABCC6 p.Arg765Trp Pathogenic ★ ⚠ same residue
ABCC6 p.Arg765Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC6 p.Arg765Leu Likely pathogenic ★ same residue
ABCC6 p.Arg765Pro Likely 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

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-arg765gln (accessed [today's date]).

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