Is ABCC6 p.Pro1247Arg (c.3740C>G) pathogenic?

ABCC6 p.Pro1247Arg (c.3740C>G) is classified Uncertain significance in ABCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.1138); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ABCC6 p.Pro1247Arg (c.3740C>G)?

ABCC6 p.Pro1247Arg (c.3740C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ABCC6 p.Pro1247Arg (c.3740C>G) in the general population?

ABCC6 p.Pro1247Arg (c.3740C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ABCC6 p.Pro1247Arg (c.3740C>G)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

ABCC6 p.Pro1247Arg

c.3740C>G · rs200242428 · VCV2037277

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 59 kb · p 0.39 · regional, not allelic
Overall
CADD	26.2	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 0.00017% European (non-Finnish) · 2/1,179,540 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,436 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.Pro1247Arg
Coding: c.3740C>G
MANE Select: NM_001171
dbSNP: rs200242428
Type: single nucleotide variant
Location: chr16:16157805 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCC6 p.Pro1247Ser Uncertain significance ★★ ⚠ same residue
ABCC6 p.Pro1247Thr Uncertain significance ★★ ⚠ same residue
ABCC6 p.Pro1247Leu Uncertain significance ★ ⚠ same residue
ABCC6 p.Ala1008Val Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala101Gly Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala1370Thr Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala1385Val Uncertain significance ★★ ⚠ same condition
ABCC6 p.Ala263Gly Uncertain significance ★★ ⚠ 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-pro1247arg (accessed [today's date]).

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