Is NEU4 p.Pro89Ser (c.265C>T) pathogenic?

NEU4 p.Pro89Ser (c.265C>T) is classified Uncertain significance in NEU4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely pathogenic (0.8481); Ultra-rare (popmax 0.08%, nfe).

How common is NEU4 p.Pro89Ser (c.265C>T) in the general population?

NEU4 p.Pro89Ser (c.265C>T) is ultra-rare (popmax 0.08%, nfe) (gnomAD).

What do computational predictors say about NEU4 p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely pathogenic (score 0.8481) — an in-silico prediction, not a clinical call.

NEU4 p.Pro89Ser

c.265C>T · rs149124108 · VCV2352945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8481 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8481	likely pathogenic
REVEL	0.768	pathogenic-leaning
SaProt	LLR -11.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,560 bp · p 0.87 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.08% European (non-Finnish) · 944/1,179,836 alleles

Filtering AF 0.0757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0741%

Overall 0.0624% 1,005/1,611,804 alleles · ultra-rare exomes 954/1,459,610 · genomes 51/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.08%	1,250
Remaining individualsnot grpmax-eligible	0.0432%	2,313
Admixed American	0.0417%	2,399
African / African-American	0.012%	8,324

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: NEU4
Protein: p.Pro89Ser
Coding: c.265C>T
MANE Select: NM_001167600
dbSNP: rs149124108
Type: single nucleotide variant
Location: chr2:241814955 (GRCh38)
Gene constraint: LOEUF 1.538 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42

Full NEU4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NEU4 c.-4+2162G>A Uncertain significance ★ same type
NEU4 p.Ala128Ser Uncertain significance ★ ⚠ same type
NEU4 p.Ala139Ser Uncertain significance ★ ⚠ same type
NEU4 p.Ala139Thr Uncertain significance ★ ⚠ same type
NEU4 p.Ala150Thr Uncertain significance ★ ⚠ same type
NEU4 p.Ala158Thr Uncertain significance ★ ⚠ same type
NEU4 p.Ala176Pro Uncertain significance ★ ⚠ same type
NEU4 p.Ala176Thr 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/neu4-p-pro89ser (accessed [today's date]).

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