Is ENPP1 p.Ser702= (c.2106T>C) pathogenic?

ENPP1 p.Ser702= (c.2106T>C) is classified Benign/Likely benign in ENPP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Low-frequency (popmax 4.52%, afr); Associated with hypophosphatemic rickets, autosomal recessive, 2.

What condition is associated with ENPP1 p.Ser702= (c.2106T>C)?

ENPP1 p.Ser702= (c.2106T>C) is associated with hypophosphatemic rickets, autosomal recessive, 2, arterial calcification, generalized, of infancy, 1 (ClinVar).

How common is ENPP1 p.Ser702= (c.2106T>C) in the general population?

ENPP1 p.Ser702= (c.2106T>C) is low-frequency (popmax 4.52%, 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.Ser702=

c.2106T>C · rs7750837 · VCV355349

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.52%, 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	<0.2	all four deltas below 0.2 · T>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.5	GERP -3.6
Overall
CADD	3.074	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.52% African / African-American · 3,365/74,412 alleles

Filtering AF 4.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.34%

Overall 0.27% 4,323/1,600,810 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.52%	22
Admixed American	0.359%	279
Remaining individualsnot grpmax-eligible	0.345%	290
Middle Eastern	0.217%	461
Ashkenazi Jewishnot grpmax-eligible	0.0827%	1,210
European (non-Finnish)	0.0417%	2,396
South Asian	0.0055%	18,185

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.Ser702=
Coding: c.2106T>C
MANE Select: NM_006208
dbSNP: rs7750837
Type: single nucleotide variant
Location: chr6:131882350 (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 702: the 'nuclease-like domain' region; a disulfide bond

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 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-ser702 (accessed [today's date]).

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