Is ENPP3 p.Arg405Cys (c.1213C>T) pathogenic?

ENPP3 p.Arg405Cys (c.1213C>T) is classified Uncertain significance in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: likely pathogenic (0.7312); Ultra-rare (popmax 0.0406%, sas).

How common is ENPP3 p.Arg405Cys (c.1213C>T) in the general population?

ENPP3 p.Arg405Cys (c.1213C>T) is ultra-rare (popmax 0.0406%, sas) (gnomAD).

What do computational predictors say about ENPP3 p.Arg405Cys (c.1213C>T)?

AlphaMissense predicts likely pathogenic (score 0.7312) — an in-silico prediction, not a clinical call.

ENPP3 p.Arg405Cys

c.1213C>T · rs533510043 · VCV2213481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7312 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0406%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7312	likely pathogenic
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -12.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 110 kb · p 0.42 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0406% South Asian · 37/91,060 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0267%

Overall 0.00527% 85/1,613,838 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0406%	2,461
Admixed American	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0048%	20,834
East Asian	0.00446%	22,428
European (non-Finnish)	0.00305%	32,774
African / African-American	0.00133%	74,970

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.Arg405Cys
Coding: c.1213C>T
MANE Select: NM_005021
dbSNP: rs533510043
Type: single nucleotide variant
Location: chr6:131685456 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50 · 3 PDB
Residue 405: a β-strand; a disulfide bond; the 'phosphodiesterase' region

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

Similar variants

ENPP3 p.Arg405His 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-arg405cys (accessed [today's date]).

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