Is ENPP3 p.Met260Ile (c.780G>A) pathogenic?

ENPP3 p.Met260Ile (c.780G>A) is classified Likely benign in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1772); Ultra-rare (popmax 0.0667%, amr).

How common is ENPP3 p.Met260Ile (c.780G>A) in the general population?

ENPP3 p.Met260Ile (c.780G>A) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

What do computational predictors say about ENPP3 p.Met260Ile (c.780G>A)?

AlphaMissense predicts likely benign (score 0.1772) — an in-silico prediction, not a clinical call.

ENPP3 p.Met260Ile

c.780G>A · VCV4249215

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1772 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1772	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -5.82	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 1.6	GERP -0.92, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 110 kb · p 0.42 · regional, not allelic
Overall
CADD	19.22	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 0.0667% Admixed American · 40/59,992 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.00887% 143/1,612,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0667%	1,500
Middle Eastern	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.024%	4,164
African / African-American	0.00933%	10,714
South Asian	0.00659%	15,177
European (non-Finnish)	0.00602%	16,605

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.Met260Ile
Coding: c.780G>A
MANE Select: NM_005021
Type: single nucleotide variant
Location: chr6:131675097 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50 · 3 PDB
Residue 260: a disulfide bond; the 'phosphodiesterase' region; an α-helix

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-met260ile (accessed [today's date]).

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