Is NOVA2 p.Lys444Arg (c.1331A>G) pathogenic?

NOVA2 p.Lys444Arg (c.1331A>G) is classified Uncertain significance in NOVA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-21). AlphaMissense: likely benign (0.3369); Ultra-rare (popmax 0.0165%, mid).

How common is NOVA2 p.Lys444Arg (c.1331A>G) in the general population?

NOVA2 p.Lys444Arg (c.1331A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NOVA2 p.Lys444Arg (c.1331A>G)?

AlphaMissense predicts likely benign (score 0.3369) — an in-silico prediction, not a clinical call.

NOVA2 p.Lys444Arg

c.1331A>G · VCV4853741

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3369	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -7.80	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 238 bp · p 4.8e-12 · regional, not allelic
Overall
CADD	27.5	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.2e-05% 1/1,614,072 alleles · ultra-rare exomes 1/1,461,832 · genomes 0/152,240 · 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.Lys444Arg
Coding: c.1331A>G
MANE Select: NM_002516
Type: single nucleotide variant
Location: chr19:45940011 (GRCh38)
Gene constraint: LOEUF 0.611 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 65.60 · 2 PDB
Residue 444: the kh 3 domain

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

Similar variants

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
NOVA2 p.Pro127= Likely 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-lys444arg (accessed [today's date]).

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