Is ABCC6 p.Val415= (c.1245G>A) pathogenic?

ABCC6 p.Val415= (c.1245G>A) is classified Benign in ABCC6 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 35.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive inherited pseudoxanthoma elasticum.

What condition is associated with ABCC6 p.Val415= (c.1245G>A)?

ABCC6 p.Val415= (c.1245G>A) is associated with autosomal recessive inherited pseudoxanthoma elasticum, pseudoxanthoma elasticum, forme fruste, arterial calcification, generalized, of infancy, 2 (ClinVar).

How is Pseudoxanthoma elasticum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ABCC6 p.Val415=

Q: How common is ABCC6 p.Val415= (c.1245G>A) in the general population?

ABCC6 p.Val415= (c.1245G>A) is common (popmax 35.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1245G>A · rs9940825 · VCV433228

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 35.2%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal recessive inherited pseudoxanthoma elasticum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.017, phastCons 1
Overall
CADD	8.443	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.2% European (non-Finnish) · 414,381/1,178,764 alleles

Filtering AF 35.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 35%

Overall 32.3% 520,718/1,611,634 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	37.1%	3
European (non-Finnish)grpmax	35.2%	3
Finnishnot grpmax-eligible	31.3%	3
Remaining individualsnot grpmax-eligible	29.6%	3
Middle Eastern	29.2%	3
Admixed American	27.6%	4
African / African-American	25.1%	4
Ashkenazi Jewishnot grpmax-eligible	22.3%	4
South Asian	21.9%	5
East Asian	9.09%	11

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val415=
Coding: c.1245G>A
MANE Select: NM_001171
dbSNP: rs9940825
Type: single nucleotide variant
Location: chr16:16198114 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.32 · 4 PDB
Residue 415: the abc transmembrane type-1 1 domain

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

Disease context

autosomal recessive inherited pseudoxanthoma elasticum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Pseudoxanthoma elasticum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ABCC6 p.Val415Met Uncertain significance ★★ ⚠ same residue
ABCC6 p.Val415Ala Uncertain significance ⚠ same residue
ABCC6 c.1868-5T>G Pathogenic/Likely pathogenic ★★ same condition
ABCC6 c.2591-1G>T Likely pathogenic ★★ same condition
ABCC6 c.2787+1G>T Pathogenic ★★ same condition
ABCC6 c.3507-1G>A Pathogenic ★★ same condition
ABCC6 c.37-1G>A Pathogenic ★★ same condition
ABCC6 c.3736-1G>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-val415 (accessed [today's date]).

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