Is NEU2 p.Ala375Pro (c.1123G>C) pathogenic?

NEU2 p.Ala375Pro (c.1123G>C) is classified Uncertain significance in NEU2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely benign (0.0868); Absent from gnomAD v4.1.

How common is NEU2 p.Ala375Pro (c.1123G>C) in the general population?

NEU2 p.Ala375Pro (c.1123G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NEU2 p.Ala375Pro (c.1123G>C)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

NEU2 p.Ala375Pro

c.1123G>C · VCV3404455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -11.91	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.28	GERP -3.3
Regional constraint	o/e 1.01	unconstrained · MANE · 2,382 bp · p 0.82 · regional, not allelic
Overall
CADD	10.24	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NEU2
Protein: p.Ala375Pro
Coding: c.1123G>C
MANE Select: NM_005383
Type: single nucleotide variant
Location: chr2:233035037 (GRCh38)
Gene constraint: LOEUF 1.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.20 · 17 PDB
Residue 375: an α-helix

Full NEU2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NEU2 p.Ala145Glu Uncertain significance ★ ⚠ same type
NEU2 p.Ala150Val Uncertain significance ★ ⚠ same type
NEU2 p.Ala178Thr Uncertain significance ★ ⚠ same type
NEU2 p.Ala17Thr Uncertain significance ★ ⚠ same type
NEU2 p.Ala222Thr Uncertain significance ★ ⚠ same type
NEU2 p.Ala333Thr Uncertain significance ★ ⚠ same type
NEU2 p.Ala38Val Uncertain significance ★ ⚠ same type
NEU2 p.Ala61Thr 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/neu2-p-ala375pro (accessed [today's date]).

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