Is NES p.Ala153Pro (c.457G>C) pathogenic?

NES p.Ala153Pro (c.457G>C) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: ambiguous (0.5423); Ultra-rare (popmax 0.0704%, afr).

How common is NES p.Ala153Pro (c.457G>C) in the general population?

NES p.Ala153Pro (c.457G>C) is ultra-rare (popmax 0.0704%, afr) (gnomAD).

What do computational predictors say about NES p.Ala153Pro (c.457G>C)?

AlphaMissense predicts ambiguous (score 0.5423) — an in-silico prediction, not a clinical call.

NES p.Ala153Pro

c.457G>C · VCV4557029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5423 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0704%, afr)

Computational evidence

Protein change
AlphaMissense	0.5423	ambiguous · top 7% in NES
REVEL	0.533	indeterminate
SaProt	LLR -12.43	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 0.0704% African / African-American · 47/66,800 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.00359% 51/1,418,774 alleles · ultra-rare exomes 28/1,266,902 · genomes 23/151,872 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0704%	1,421
Remaining individualsnot grpmax-eligible	0.00552%	18,131
Finnishnot grpmax-eligible	0.00238%	41,950

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: NES
Protein: p.Ala153Pro
Coding: c.457G>C
MANE Select: NM_006617
Type: single nucleotide variant
Location: chr1:156676808 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 153: the if rod domain; the 'linker 12' 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-ala153pro (accessed [today's date]).

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