Is DNA2 p.Ala874Val (c.2621C>T) pathogenic?

DNA2 p.Ala874Val (c.2621C>T) is classified Uncertain significance in DNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-24). AlphaMissense: likely benign (0.111); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with DNA2 p.Ala874Val (c.2621C>T)?

DNA2 p.Ala874Val (c.2621C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNA2 p.Ala874Val (c.2621C>T) in the general population?

DNA2 p.Ala874Val (c.2621C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about DNA2 p.Ala874Val (c.2621C>T)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

DNA2 p.Ala874Val

c.2621C>T · rs866536175 · VCV2492790

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -4.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.6	GERP 0.35, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	18.14	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 0.0107% African / African-American · 8/74,914 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000682% 11/1,613,678 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,364
Remaining individualsnot grpmax-eligible	0.0032%	31,231
European (non-Finnish)	8.48e-05%	1,179,830

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.Ala874Val
Coding: c.2621C>T
MANE Select: NM_001080449
dbSNP: rs866536175
Type: single nucleotide variant
Location: chr10:68422301 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 874: the upf1-type sf1b helicase c-terminal domain; the 'helicase 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.Ala874Thr 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.Arg135Gln 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-ala874val (accessed [today's date]).

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