Is ENPP3 p.Ala837= (c.2511C>G) pathogenic?

ENPP3 p.Ala837= (c.2511C>G) is classified Likely benign in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-23). Ultra-rare (popmax 0.0987%, mid).

How common is ENPP3 p.Ala837= (c.2511C>G) in the general population?

ENPP3 p.Ala837= (c.2511C>G) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

ENPP3 p.Ala837=

c.2511C>G · rs148724029 · VCV734966

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

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 -2.8	GERP -3.9
Overall
CADD	2.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0987% Middle Eastern · 6/6,078 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.0147% 237/1,613,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0987%	1,013
European (non-Finnish)	0.0188%	5,314
Remaining individualsnot grpmax-eligible	0.00801%	12,490
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,580
Admixed American	0.00335%	29,887
African / African-American	0.00134%	74,856

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: ENPP3
Protein: p.Ala837=
Coding: c.2511C>G
MANE Select: NM_005021
dbSNP: rs148724029
Type: single nucleotide variant
Location: chr6:131746839 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50 · 3 PDB
Residue 837: the 'nuclease' region

Full ENPP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP3 c.762+4T>C Likely benign ★★ same type
CTAGE9 p.Ala668Thr Uncertain significance ★ ⚠ same type
CTAGE9 p.Asp478Tyr Uncertain significance ★ ⚠ same type
CTAGE9 p.Glu332Lys Uncertain significance ★ ⚠ same type
CTAGE9 p.Glu414Asp Uncertain significance ★ ⚠ same type
CTAGE9 p.Ile207Thr Uncertain significance ★ ⚠ same type
ENPP3 p.Ala248Asp Uncertain significance ★ ⚠ same type
ENPP3 p.Ala330Pro Uncertain significance ★ ⚠ same type

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/enpp3-p-ala837 (accessed [today's date]).

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