Is ENPP3 p.Arg405His (c.1214G>A) pathogenic?

ENPP3 p.Arg405His (c.1214G>A) is classified Uncertain significance in ENPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: ambiguous (0.524); Ultra-rare (popmax 0.0165%, sas).

How common is ENPP3 p.Arg405His (c.1214G>A) in the general population?

ENPP3 p.Arg405His (c.1214G>A) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about ENPP3 p.Arg405His (c.1214G>A)?

AlphaMissense predicts ambiguous (score 0.524) — an in-silico prediction, not a clinical call.

ENPP3 p.Arg405His

c.1214G>A · VCV3844973

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.524 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.524	ambiguous
REVEL	0.743	pathogenic-leaning
SaProt	LLR -10.01	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 0.76, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 110 kb · p 0.42 · regional, not allelic
Overall
CADD	31.0	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 0.0165% South Asian · 15/91,058 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.0075% 121/1,613,594 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.142%	705
Remaining individualsnot grpmax-eligible	0.0192%	5,205
South Asiangrpmax	0.0165%	6,071
African / African-American	0.00535%	18,709
European (non-Finnish)	0.0039%	25,649
Finnishnot grpmax-eligible	0.00313%	31,986

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg405His
Coding: c.1214G>A
MANE Select: NM_005021
Type: single nucleotide variant
Location: chr6:131685457 (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.Arg405Cys 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-arg405his (accessed [today's date]).

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