Is DNA2 p.Val282Ala (c.845T>C) pathogenic?

DNA2 p.Val282Ala (c.845T>C) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-02). AlphaMissense: ambiguous (0.4742); Very rare (popmax 0.00445%, sas); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Val282Ala (c.845T>C)?

DNA2 p.Val282Ala (c.845T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Val282Ala (c.845T>C) in the general population?

DNA2 p.Val282Ala (c.845T>C) is very rare (popmax 0.00445%, sas) (gnomAD).

What do computational predictors say about DNA2 p.Val282Ala (c.845T>C)?

AlphaMissense predicts ambiguous (score 0.4742) — an in-silico prediction, not a clinical call.

DNA2 p.Val282Ala

c.845T>C · rs749245151 · VCV2964817

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4742	ambiguous
REVEL	0.711	pathogenic-leaning
SaProt	LLR -8.26	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	26.0	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

Grpmax group 0.00445% South Asian · 4/89,808 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000901%

Overall 0.00118% 19/1,606,462 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00445%	22,452
Admixed American	0.0017%	58,792
Remaining individualsnot grpmax-eligible	0.00161%	62,266
European (non-Finnish)	0.00111%	90,454

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.Val282Ala
Coding: c.845T>C
MANE Select: NM_001080449
dbSNP: rs749245151
Type: single nucleotide variant
Location: chr10:68450122 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 282: 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 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
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-val282ala (accessed [today's date]).

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