Is NES p.Ala110Asp (c.329C>A) pathogenic?

NES p.Ala110Asp (c.329C>A) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.2674); Rare (popmax 0.176%, mid).

How common is NES p.Ala110Asp (c.329C>A) in the general population?

NES p.Ala110Asp (c.329C>A) is rare (popmax 0.176%, mid) (gnomAD).

What do computational predictors say about NES p.Ala110Asp (c.329C>A)?

AlphaMissense predicts likely benign (score 0.2674) — an in-silico prediction, not a clinical call.

NES p.Ala110Asp

c.329C>A · VCV4557036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2674 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.176%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2674	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 0.37, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	24.2	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 0.176% Middle Eastern · 10/5,672 alleles

Filtering AF 0.0956% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0728%

Overall 0.0029% 45/1,553,286 alleles · rare exomes 40/1,401,174 · genomes 5/152,112 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.176%	567
Admixed American	0.0205%	4,877
Remaining individualsnot grpmax-eligible	0.0149%	6,717
European (non-Finnish)	0.0013%	77,214

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.Ala110Asp
Coding: c.329C>A
MANE Select: NM_006617
Type: single nucleotide variant
Location: chr1:156676936 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 110: the if rod domain; the 'coil 1b' 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-ala110asp (accessed [today's date]).

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