Is DNA2 p.Thr430Ile (c.1289C>T) pathogenic?

DNA2 p.Thr430Ile (c.1289C>T) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.1982); Very rare (popmax 0.0023%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Thr430Ile (c.1289C>T)?

DNA2 p.Thr430Ile (c.1289C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Thr430Ile (c.1289C>T) in the general population?

DNA2 p.Thr430Ile (c.1289C>T) is very rare (popmax 0.0023%, nfe) (gnomAD).

What do computational predictors say about DNA2 p.Thr430Ile (c.1289C>T)?

AlphaMissense predicts likely benign (score 0.1982) — an in-silico prediction, not a clinical call.

DNA2 p.Thr430Ile

c.1289C>T · rs1372830778 · VCV2691496

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1982	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	20.3	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 0.0023% European (non-Finnish) · 27/1,171,974 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00169% 27/1,599,014 alleles · very rare

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: DNA2
Protein: p.Thr430Ile
Coding: c.1289C>T
MANE Select: NM_001080449
dbSNP: rs1372830778
Type: single nucleotide variant
Location: chr10:68443043 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 430: the 'nuclease activity' region

Full DNA2 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

DNA2 p.Thr430Ala Uncertain significance ★ ⚠ same residue
DNA2 c.2402+1G>A Uncertain significance ★★ same condition
DNA2 p.Ala1003Ser Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala346Val Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala51Val Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala667Ser Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala819Val Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala874Thr 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/dna2-p-thr430ile (accessed [today's date]).

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