Is NES p.Thr668Pro (c.2002A>C) pathogenic?

NES p.Thr668Pro (c.2002A>C) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.1107); Rare (popmax 0.188%, sas).

How common is NES p.Thr668Pro (c.2002A>C) in the general population?

NES p.Thr668Pro (c.2002A>C) is rare (popmax 0.188%, sas) (gnomAD).

What do computational predictors say about NES p.Thr668Pro (c.2002A>C)?

AlphaMissense predicts likely benign (score 0.1107) — an in-silico prediction, not a clinical call.

NES p.Thr668Pro

c.2002A>C · rs201574820 · VCV3193873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1107 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.188%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1107	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -7.76	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 -0.62	GERP -2.8
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	7.941	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 0.188% South Asian · 170/90,448 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.156%

Overall 0.0125% 202/1,610,760 alleles · rare exomes 188/1,458,444 · genomes 14/152,316 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.188%	532
Middle Eastern	0.0663%	1,509
Remaining individualsnot grpmax-eligible	0.00962%	10,394
European (non-Finnish)	0.00178%	56,156
African / African-American	0.00134%	74,726

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.Thr668Pro
Coding: c.2002A>C
MANE Select: NM_006617
dbSNP: rs201574820
Type: single nucleotide variant
Location: chr1:156672186 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 668: the 'tail' 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-thr668pro (accessed [today's date]).

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