Is ENPP3 p.Val620Met (c.1858G>A) pathogenic?

ENPP3 p.Val620Met (c.1858G>A) is classified Benign in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0762); Common (popmax 7.15%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ENPP3 p.Val620Met (c.1858G>A)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

ENPP3 p.Val620Met

Q: How common is ENPP3 p.Val620Met (c.1858G>A) in the general population?

ENPP3 p.Val620Met (c.1858G>A) is common (popmax 7.15%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1858G>A · rs9321309 · VCV788295

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.15%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP -3.2, phastCons 0.007
Regional constraint	o/e 0.98	unconstrained · MANE · 110 kb · p 0.42 · regional, not allelic
Overall
CADD	8.82	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.15% African / African-American · 5,361/74,972 alleles

Filtering AF 6.99% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.93%

Overall 0.382% 6,156/1,613,084 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.15%	14
Admixed American	0.573%	174
Remaining individualsnot grpmax-eligible	0.482%	208
Middle Eastern	0.462%	216
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,289
South Asian	0.0121%	8,278
European (non-Finnish)	0.00857%	11,674
East Asian	0.00223%	44,878

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.Val620Met
Coding: c.1858G>A
MANE Select: NM_005021
dbSNP: rs9321309
Type: single nucleotide variant
Location: chr6:131726105 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50 · 3 PDB
Residue 620: a disulfide bond; a UniProt-annotated variant site (in); the 'nuclease' region

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

Similar variants

ENPP3 p.Val620Leu Uncertain significance ★ ⚠ same residue
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

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-val620met (accessed [today's date]).

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