Is ABCC6 p.Arg1357Pro (c.4070G>C) pathogenic?

ABCC6 p.Arg1357Pro (c.4070G>C) is classified Likely pathogenic in ABCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). AlphaMissense: likely pathogenic (0.719); Very rare (popmax 0.00133%, afr).

How common is ABCC6 p.Arg1357Pro (c.4070G>C) in the general population?

ABCC6 p.Arg1357Pro (c.4070G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ABCC6 p.Arg1357Pro (c.4070G>C)?

AlphaMissense predicts likely pathogenic (score 0.719) — an in-silico prediction, not a clinical call.

ABCC6 p.Arg1357Pro

c.4070G>C · rs201275608 · VCV2040203

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.719	likely pathogenic ✓ concordant with ClinVar · top 9% in ABCC6
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -13.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.7	GERP 0.82, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	29.7	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 0.00133% African / African-American · 1/75,028 alleles

Overall 6.85e-05% 1/1,460,230 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.Arg1357Pro
Coding: c.4070G>C
MANE Select: NM_001171
dbSNP: rs201275608
Type: single nucleotide variant
Location: chr16:16154766 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 1357: a UniProt-annotated variant site (in pxe); an α-helix; the abc transporter 2 domain

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

Similar variants

ABCC6 p.Arg1357Leu Likely pathogenic ★ ⚠ same residue
ABCC6 p.Arg1357Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC6 p.Arg1357Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC6 p.Arg1357= Likely benign ★ 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-arg1357pro (accessed [today's date]).

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