Is NOVA2 p.Pro230Leu (c.689C>T) pathogenic?

NOVA2 p.Pro230Leu (c.689C>T) is classified Uncertain significance in NOVA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely pathogenic (0.9927); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities.

How common is NOVA2 p.Pro230Leu (c.689C>T) in the general population?

NOVA2 p.Pro230Leu (c.689C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOVA2 p.Pro230Leu (c.689C>T)?

AlphaMissense predicts likely pathogenic (score 0.9927) — an in-silico prediction, not a clinical call.

NOVA2 p.Pro230Leu

Q: What condition is associated with NOVA2 p.Pro230Leu (c.689C>T)?

NOVA2 p.Pro230Leu (c.689C>T) is associated with neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (ClinVar).

c.689C>T · rs2513852720 · VCV3065993

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9927 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.9927	likely pathogenic
REVEL	0.319	indeterminate
SaProt	LLR -6.97	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 33 kb · p 1.6e-21 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOVA2
Protein: p.Pro230Leu
Coding: c.689C>T
MANE Select: NM_002516
dbSNP: rs2513852720
Type: single nucleotide variant
Location: chr19:45940653 (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

Disease context

neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOVA2 p.Ala287= Benign ★★ same condition
NOVA2 p.Leu238= Benign ★★ same condition
NOVA2 p.Gly31Ala Uncertain significance ★ ⚠ same condition
NOVA2 p.Thr124Met Conflicting classifications of pathogenicity ★ ⚠ same condition
NOVA2 p.Val156Met Conflicting classifications of pathogenicity ★ ⚠ same condition
NOVA2 p.Gly219fs Likely pathogenic ★ same condition
NOVA2 p.Leu175fs Pathogenic ★ same condition
NOVA2 p.Tyr330fs Pathogenic ★ same condition

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-pro230leu (accessed [today's date]).

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