Is ENPP6 p.Asp183Glu (c.549C>A) pathogenic?

ENPP6 p.Asp183Glu (c.549C>A) is classified Uncertain significance in ENPP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.4966); Ultra-rare (popmax 0.0433%, amr).

How common is ENPP6 p.Asp183Glu (c.549C>A) in the general population?

ENPP6 p.Asp183Glu (c.549C>A) is ultra-rare (popmax 0.0433%, amr) (gnomAD).

What do computational predictors say about ENPP6 p.Asp183Glu (c.549C>A)?

AlphaMissense predicts ambiguous (score 0.4966) — an in-silico prediction, not a clinical call.

ENPP6 p.Asp183Glu

c.549C>A · VCV4249242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4966 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, amr)

Computational evidence

Protein change
AlphaMissense	0.4966	ambiguous
REVEL	0.387	indeterminate
SaProt	LLR -6.54	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 127 kb · p 0.96 · regional, not allelic
Overall
CADD	17.29	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 0.0433% Admixed American · 26/60,026 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00229% 37/1,614,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0433%	2,309
Remaining individualsnot grpmax-eligible	0.0144%	6,945
African / African-American	0.00133%	75,048
European (non-Finnish)	8.47e-05%	1,180,026

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: ENPP6
Protein: p.Asp183Glu
Coding: c.549C>A
MANE Select: NM_153343
Type: single nucleotide variant
Location: chr4:184117885 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06

Full ENPP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP6 p.Asp183His Uncertain significance ★ ⚠ same residue
ENPP6 p.Ser71= Benign ★★ same type
ENPP6 p.Ala20Asp Uncertain significance ★ ⚠ same type
ENPP6 p.Ala20Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala212Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala303Pro Uncertain significance ★ ⚠ same type
ENPP6 p.Ala369Gly Uncertain significance ★ ⚠ same type
ENPP6 p.Ala380Pro 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/enpp6-p-asp183glu (accessed [today's date]).

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