Is NEU2 p.Ser288Cys (c.863C>G) pathogenic?

NEU2 p.Ser288Cys (c.863C>G) is classified Uncertain significance in NEU2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.0824); Ultra-rare (popmax 0.0235%, nfe).

How common is NEU2 p.Ser288Cys (c.863C>G) in the general population?

NEU2 p.Ser288Cys (c.863C>G) is ultra-rare (popmax 0.0235%, nfe) (gnomAD).

What do computational predictors say about NEU2 p.Ser288Cys (c.863C>G)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

NEU2 p.Ser288Cys

c.863C>G · VCV4118911

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP 0.82, phastCons 0.002
Regional constraint	o/e 1.01	unconstrained · MANE · 2,382 bp · p 0.82 · regional, not allelic
Overall
CADD	9.992	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0235% European (non-Finnish) · 269/1,143,478 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0202%

Overall 0.0187% 289/1,541,850 alleles · ultra-rare exomes 278/1,389,580 · genomes 11/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0235%	4,251
Finnishnot grpmax-eligible	0.0213%	4,705
Remaining individualsnot grpmax-eligible	0.0118%	8,467

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: NEU2
Protein: p.Ser288Cys
Coding: c.863C>G
MANE Select: NM_005383
Type: single nucleotide variant
Location: chr2:233034777 (GRCh38)
Gene constraint: LOEUF 1.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.20 · 17 PDB

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.Ala375Pro Uncertain significance ★ ⚠ same type
NEU2 p.Ala38Val 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-ser288cys (accessed [today's date]).

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