Is NES p.Leu560Pro (c.1679T>C) pathogenic?

NES p.Leu560Pro (c.1679T>C) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.0907); Rare (popmax 0.977%, afr).

How common is NES p.Leu560Pro (c.1679T>C) in the general population?

NES p.Leu560Pro (c.1679T>C) is rare (popmax 0.977%, afr) (gnomAD).

What do computational predictors say about NES p.Leu560Pro (c.1679T>C)?

AlphaMissense predicts likely benign (score 0.0907) — an in-silico prediction, not a clinical call.

NES p.Leu560Pro

c.1679T>C · VCV4118866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0907 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.977%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0907	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -12.31	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 -0.17	GERP -2.3
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	14.19	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 0.977% African / African-American · 732/74,946 alleles

Filtering AF 0.918% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.895%

Overall 0.0478% 772/1,613,378 alleles · rare exomes 377/1,461,200 · genomes 395/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.977%	102
Remaining individualsnot grpmax-eligible	0.0304%	3,288
Admixed American	0.0217%	4,611
South Asian	0.0011%	90,992
European (non-Finnish)	0.000593%	168,536

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.Leu560Pro
Coding: c.1679T>C
MANE Select: NM_006617
Type: single nucleotide variant
Location: chr1:156672509 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 560: the 'tail' region

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

Similar variants

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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-leu560pro (accessed [today's date]).

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