Is ABCC6 p.Arg765Leu (c.2294G>T) pathogenic?

ABCC6 p.Arg765Leu (c.2294G>T) is classified Likely pathogenic in ABCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-18). AlphaMissense: likely pathogenic (0.6865); Very rare (popmax 0.000424%, nfe).

How common is ABCC6 p.Arg765Leu (c.2294G>T) in the general population?

ABCC6 p.Arg765Leu (c.2294G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ABCC6 p.Arg765Leu (c.2294G>T)?

AlphaMissense predicts likely pathogenic (score 0.6865) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg765Leu

c.2294G>T · rs67561842 · VCV1520297

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6865	likely pathogenic ✓ concordant with ClinVar · top 10% in ABCC6
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -15.29	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 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	26.8	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 0.000424% European (non-Finnish) · 5/1,180,016 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,244 alleles · very rare

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.Arg765Leu
Coding: c.2294G>T
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

Similar variants

ABCC6 p.Arg765Gln Pathogenic ★★ ⚠ same residue
ABCC6 p.Arg765Pro Likely pathogenic ★ same residue
ABCC6 p.Arg765Trp Pathogenic ★ ⚠ same residue
ABCC6 p.Arg765Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same type
ABCC6 c.2071-1G>A Likely pathogenic ★★ same type
ABCC6 c.2591-1G>T Likely pathogenic ★★ same type
ABCC6 c.2787+1G>T Pathogenic ★★ same type

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-arg765leu (accessed [today's date]).

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