Is NOVA2 p.Val85Ile (c.253G>A) pathogenic?

NOVA2 p.Val85Ile (c.253G>A) is classified Uncertain significance in NOVA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-06). AlphaMissense: likely benign (0.0846); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with NOVA2 p.Val85Ile (c.253G>A)?

NOVA2 p.Val85Ile (c.253G>A) is associated with Inborn genetic diseases (ClinVar).

How common is NOVA2 p.Val85Ile (c.253G>A) in the general population?

NOVA2 p.Val85Ile (c.253G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NOVA2 p.Val85Ile (c.253G>A)?

AlphaMissense predicts likely benign (score 0.0846) — an in-silico prediction, not a clinical call.

NOVA2 p.Val85Ile

c.253G>A · rs2513860709 · VCV3201425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0846	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.33	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 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 33 kb · p 1.6e-21 · regional, not allelic
Overall
CADD	21.2	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 0.00223% East Asian · 1/44,884 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,188 alleles · very rare exomes 3/1,461,874 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
European (non-Finnish)	0.000169%	590,012

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.Val85Ile
Coding: c.253G>A
MANE Select: NM_002516
dbSNP: rs2513860709
Type: single nucleotide variant
Location: chr19:45953923 (GRCh38)
Gene constraint: LOEUF 0.611 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 65.60 · 2 PDB
Residue 85: the kh 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOVA2 p.Ala247Thr Uncertain significance ★★ ⚠ same condition
NOVA2 p.Asn292Thr Likely benign ★★ same condition
NOVA2 p.Ala240Thr Uncertain significance ★ ⚠ same condition
NOVA2 p.Ala248Pro Uncertain significance ★ ⚠ same condition
NOVA2 p.Ala331Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
NOVA2 p.Ala334Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
NOVA2 p.Ala339Pro Uncertain significance ★ ⚠ same condition
NOVA2 p.Ala362Thr Uncertain significance ★ ⚠ 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-val85ile (accessed [today's date]).

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