Is NES p.Pro469Ala (c.1405C>G) pathogenic?

NES p.Pro469Ala (c.1405C>G) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.0543); Absent from gnomAD v4.1.

How common is NES p.Pro469Ala (c.1405C>G) in the general population?

NES p.Pro469Ala (c.1405C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NES p.Pro469Ala (c.1405C>G)?

AlphaMissense predicts likely benign (score 0.0543) — an in-silico prediction, not a clinical call.

NES p.Pro469Ala

c.1405C>G · rs2524872252 · VCV2615888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0543 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0543	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -6.07	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 -0.046	GERP -3.5, phastCons 0.098
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	5.338	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

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: NES
Protein: p.Pro469Ala
Coding: c.1405C>G
MANE Select: NM_006617
dbSNP: rs2524872252
Type: single nucleotide variant
Location: chr1:156672783 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 469: the 'tail' region; the 'disordered' region

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

Similar variants

NES p.Glu8Val Uncertain significance ★★ ⚠ same type
NES p.Arg342Gln Benign ★★ same type
NES p.Glu609Gln Benign ★★ same type
NES p.Gly1407Arg Benign ★★ same type
NES p.Leu412= Benign ★★ same type
NES p.Lys830Arg Benign ★★ same type
NES p.Pro1275Leu Benign ★★ same type
NES p.Ser1466Gly Benign ★★ 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/nes-p-pro469ala (accessed [today's date]).

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