Is ENPP1 p.Ala352= (c.1056T>G) pathogenic?

ENPP1 p.Ala352= (c.1056T>G) is classified Conflicting classifications of pathogenicity in ENPP1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-17). Rare (popmax 0.369%, afr); Associated with arterial calcification, generalized, of infancy, 1.

What condition is associated with ENPP1 p.Ala352= (c.1056T>G)?

ENPP1 p.Ala352= (c.1056T>G) is associated with arterial calcification, generalized, of infancy, 1, hypophosphatemic rickets, autosomal recessive, 2 (ClinVar).

How common is ENPP1 p.Ala352= (c.1056T>G) in the general population?

ENPP1 p.Ala352= (c.1056T>G) is rare (popmax 0.369%, afr) (gnomAD).

How is Generalized arterial calcification of infancy inherited?

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

ENPP1 p.Ala352=

c.1056T>G · rs150279426 · VCV193688

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.369%, afr)

Conditions

arterial calcification, generalized, of infancy, 1

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 -0.84	GERP -3.9
Overall
CADD	9.062	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.369% African / African-American · 277/74,986 alleles

Filtering AF 0.334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.32%

Overall 0.0278% 447/1,610,424 alleles · rare exomes 280/1,458,076 · genomes 167/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.369%	271
Middle Eastern	0.166%	602
Admixed American	0.0683%	1,464
Remaining individualsnot grpmax-eligible	0.0513%	1,950
European (non-Finnish)	0.00731%	13,684
South Asian	0.0011%	90,960

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: ENPP1
Protein: p.Ala352=
Coding: c.1056T>G
MANE Select: NM_006208
dbSNP: rs150279426
Type: single nucleotide variant
Location: chr6:131864536 (GRCh38)
Gene constraint: LOEUF 0.729 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.35 · 7 PDB
Residue 352: an α-helix; the 'phosphodiesterase' region

Full ENPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arterial calcification, generalized, of infancy, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypophosphatemic rickets, autosomal recessive, 2

For Generalized arterial calcification of infancy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

ENPP1 c.2230+1G>A Pathogenic ★★ same condition
ENPP1 c.2608-1G>A Likely pathogenic ★★ same condition
ENPP1 c.313+1G>A Pathogenic/Likely pathogenic ★★ same condition
ENPP1 p.Arg456Ter Pathogenic/Likely pathogenic ★★ same condition
ENPP1 p.Arg476Ter Pathogenic ★★ same condition
ENPP1 p.Arg481Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ENPP1 p.Arg782Ter Pathogenic ★★ same condition
ENPP1 p.Glu866Lys Likely 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/enpp1-p-ala352 (accessed [today's date]).

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