Is DNA2 p.Ile96Thr (c.287T>C) pathogenic?

DNA2 p.Ile96Thr (c.287T>C) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.2214); Ultra-rare (popmax 0.0361%, afr); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Ile96Thr (c.287T>C)?

DNA2 p.Ile96Thr (c.287T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Ile96Thr (c.287T>C) in the general population?

DNA2 p.Ile96Thr (c.287T>C) is ultra-rare (popmax 0.0361%, afr) (gnomAD).

What do computational predictors say about DNA2 p.Ile96Thr (c.287T>C)?

AlphaMissense predicts likely benign (score 0.2214) — an in-silico prediction, not a clinical call.

DNA2 p.Ile96Thr

c.287T>C · rs373811580 · VCV449765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2214 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0361%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2214	likely benign
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -7.66	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	25.2	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 0.0361% African / African-American · 27/74,862 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00342% 55/1,607,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0361%	2,773
Remaining individualsnot grpmax-eligible	0.0353%	2,831
East Asian	0.00671%	14,902
European (non-Finnish)	0.000255%	392,505

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.Ile96Thr
Coding: c.287T>C
MANE Select: NM_001080449
dbSNP: rs373811580
Type: single nucleotide variant
Location: chr10:68468277 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 96: 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

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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
DNA2 p.Ala874Val 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-ile96thr (accessed [today's date]).

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