Is NOVA2 p.Glu4Lys (c.10G>A) pathogenic?

NOVA2 p.Glu4Lys (c.10G>A) is classified Uncertain significance in NOVA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). AlphaMissense: likely pathogenic (0.6438); Very rare (popmax 8.15e-05%).

How common is NOVA2 p.Glu4Lys (c.10G>A) in the general population?

NOVA2 p.Glu4Lys (c.10G>A) is very rare (popmax 8.15e-05%) (gnomAD).

What do computational predictors say about NOVA2 p.Glu4Lys (c.10G>A)?

AlphaMissense predicts likely pathogenic (score 0.6438) — an in-silico prediction, not a clinical call.

NOVA2 p.Glu4Lys

c.10G>A · VCV3370885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.15e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6438	likely pathogenic
REVEL	0.079	moderately benign-leaning
SaProt	LLR -8.80	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 0.31, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 33 kb · p 1.6e-21 · regional, not allelic
Overall
CADD	22.3	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 8.15e-05%

Overall 8.15e-05% 1/1,226,586 alleles · very rare exomes 1/1,081,416 · genomes 0/145,170 · joint denominator

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: NOVA2
Protein: p.Glu4Lys
Coding: c.10G>A
MANE Select: NM_002516
Type: single nucleotide variant
Location: chr19:45973342 (GRCh38)
Gene constraint: LOEUF 0.611 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 65.60 · 2 PDB

Full NOVA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOVA2 p.Glu4= Likely benign ★ same residue
NOVA2 p.Ala247Thr Uncertain significance ★★ ⚠ same type
NOVA2 p.Ala287= Benign ★★ same type
NOVA2 p.Ala383= Benign/Likely benign ★★ same type
NOVA2 p.Asn292Thr Likely benign ★★ same type
NOVA2 p.Ile39= Benign/Likely benign ★★ same type
NOVA2 p.Leu135= Likely benign ★★ same type
NOVA2 p.Leu238= 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/nova2-p-glu4lys (accessed [today's date]).

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