Is ENPP5 p.Ala344= (c.1032G>A) pathogenic?

ENPP5 p.Ala344= (c.1032G>A) is classified Likely benign in ENPP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). Ultra-rare (popmax 0.0505%, sas).

How common is ENPP5 p.Ala344= (c.1032G>A) in the general population?

ENPP5 p.Ala344= (c.1032G>A) is ultra-rare (popmax 0.0505%, sas) (gnomAD).

ENPP5 p.Ala344=

c.1032G>A · VCV4249235

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -5.6
Overall
CADD	6.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0505% South Asian · 46/91,068 alleles

Filtering AF 0.0389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0348%

Overall 0.0125% 201/1,611,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0505%	1,980
European (non-Finnish)	0.0119%	8,427
Remaining individualsnot grpmax-eligible	0.0112%	8,925
African / African-American	0.0107%	9,363

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: ENPP5
Protein: p.Ala344=
Coding: c.1032G>A
MANE Select: NM_001290072
Type: single nucleotide variant
Location: chr6:46161728 (GRCh38)
Gene constraint: LOEUF 1.113 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.56 · 1 PDB

Full ENPP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP5 p.Ala270Val Uncertain significance ★ ⚠ same type
ENPP5 p.Ala402Ser Uncertain significance ★ ⚠ same type
ENPP5 p.Ala423Thr Uncertain significance ★ ⚠ same type
ENPP5 p.Asn232Thr Uncertain significance ★ ⚠ same type
ENPP5 p.Asn310Lys Uncertain significance ★ ⚠ same type
ENPP5 p.Asn338Lys Uncertain significance ★ ⚠ same type
ENPP5 p.Asn382Ser Uncertain significance ★ ⚠ same type
ENPP5 p.Asn66Asp 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/enpp5-p-ala344 (accessed [today's date]).

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