Is ENPP1 p.Pro919= (c.2757A>T) pathogenic?

ENPP1 p.Pro919= (c.2757A>T) is classified Conflicting classifications of pathogenicity in ENPP1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Rare (popmax 0.624%, afr); Associated with hypophosphatemic rickets, autosomal recessive, 2.

What condition is associated with ENPP1 p.Pro919= (c.2757A>T)?

ENPP1 p.Pro919= (c.2757A>T) is associated with hypophosphatemic rickets, autosomal recessive, 2, arterial calcification, generalized, of infancy, 1 (ClinVar).

How common is ENPP1 p.Pro919= (c.2757A>T) in the general population?

ENPP1 p.Pro919= (c.2757A>T) is rare (popmax 0.624%, afr) (gnomAD).

How is Autosomal recessive hypophosphatemic rickets inherited?

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

ENPP1 p.Pro919=

c.2757A>T · rs73541508 · VCV355354

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.624%, afr)

Conditions

hypophosphatemic rickets, autosomal recessive, 2

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 3.9	GERP 0.056, phastCons 1
Overall
CADD	8.978	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.624% African / African-American · 468/75,054 alleles

Filtering AF 0.577% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.558%

Overall 0.0319% 515/1,614,066 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.624%	160
Admixed American	0.0333%	3,001
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Middle Eastern	0.0165%	6,060
South Asian	0.0011%	91,078
European (non-Finnish)	0.000509%	196,649

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.Pro919=
Coding: c.2757A>T
MANE Select: NM_006208
dbSNP: rs73541508
Type: single nucleotide variant
Location: chr6:131890490 (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 919: the 'nuclease-like domain' region; an α-helix

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

Disease context

hypophosphatemic rickets, autosomal recessive, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arterial calcification, generalized, of infancy, 1

For Autosomal recessive hypophosphatemic rickets (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ENPP1 p.Pro919Leu Uncertain significance ★ ⚠ same residue
ENPP1 p.Pro919Ser Uncertain significance ★ ⚠ same residue
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

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-pro919 (accessed [today's date]).

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