Is ENPP4 p.Asp252His (c.754G>C) pathogenic?

ENPP4 p.Asp252His (c.754G>C) is classified Uncertain significance in ENPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.2106); Ultra-rare (popmax 0.0166%, mid).

How common is ENPP4 p.Asp252His (c.754G>C) in the general population?

ENPP4 p.Asp252His (c.754G>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ENPP4 p.Asp252His (c.754G>C)?

AlphaMissense predicts likely benign (score 0.2106) — an in-silico prediction, not a clinical call.

ENPP4 p.Asp252His

c.754G>C · VCV4249230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2106	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -10.66	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,307 bp · p 0.86 · regional, not allelic
Overall
CADD	23.3	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 0.0166% Middle Eastern · 1/6,040 alleles

Overall 6.85e-05% 1/1,459,632 alleles · ultra-rare

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: ENPP4
Protein: p.Asp252His
Coding: c.754G>C
MANE Select: NM_014936
Type: single nucleotide variant
Location: chr6:46140337 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.49 · 2 PDB
Residue 252: an α-helix

Full ENPP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP4 p.Ala181Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala190Glu Uncertain significance ★ ⚠ same type
ENPP4 p.Ala190Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala355Gly Uncertain significance ★ ⚠ same type
ENPP4 p.Ala355Ser Uncertain significance ★ ⚠ same type
ENPP4 p.Ala409Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala409Val Uncertain significance ★ ⚠ same type
ENPP4 p.Ala90Ser 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/enpp4-p-asp252his (accessed [today's date]).

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