Is NES p.Phe10Cys (c.29T>G) pathogenic?

NES p.Phe10Cys (c.29T>G) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-08). AlphaMissense: likely pathogenic (0.6075); Rare (popmax 0.781%, eas).

How common is NES p.Phe10Cys (c.29T>G) in the general population?

NES p.Phe10Cys (c.29T>G) is rare (popmax 0.781%, eas) (gnomAD).

What do computational predictors say about NES p.Phe10Cys (c.29T>G)?

AlphaMissense predicts likely pathogenic (score 0.6075) — an in-silico prediction, not a clinical call.

NES p.Phe10Cys

c.29T>G · rs1647334099 · VCV2393969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6075 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.781%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6075	likely pathogenic · top 6% in NES
REVEL	0.474	indeterminate
SaProt	LLR -5.47	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	25.0	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 0.781% East Asian · 311/39,840 alleles

Filtering AF 0.709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.681%

Overall 0.157% 2,416/1,542,596 alleles · rare exomes 2,415/1,391,438 · genomes 1/151,158 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.781%	128
Ashkenazi Jewishnot grpmax-eligible	0.501%	200
Remaining individualsnot grpmax-eligible	0.354%	282
Middle Eastern	0.28%	358
Finnishnot grpmax-eligible	0.205%	487
African / African-American	0.158%	632
European (non-Finnish)	0.126%	791
Admixed American	0.122%	817
South Asian	0.0178%	5,624

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.Phe10Cys
Coding: c.29T>G
MANE Select: NM_006617
dbSNP: rs1647334099
Type: single nucleotide variant
Location: chr1:156677236 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 10: the if rod domain; the 'coil 1a' 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-phe10cys (accessed [today's date]).

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