Is DNA2 p.Cys718Phe (c.2153G>T) pathogenic?

DNA2 p.Cys718Phe (c.2153G>T) is classified Benign/Likely benign in DNA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1064); Rare (popmax 0.37%, nfe).

How common is DNA2 p.Cys718Phe (c.2153G>T) in the general population?

DNA2 p.Cys718Phe (c.2153G>T) is rare (popmax 0.37%, nfe) (gnomAD).

What do computational predictors say about DNA2 p.Cys718Phe (c.2153G>T)?

AlphaMissense predicts likely benign (score 0.1064) — an in-silico prediction, not a clinical call.

DNA2 p.Cys718Phe

c.2153G>T · rs147096750 · VCV449651

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1064 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.37%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1064	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -8.61	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 3.3	GERP -0.24, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 57 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.7	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 0.37% European (non-Finnish) · 4,364/1,178,934 alleles

Filtering AF 0.361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.357%

Overall 0.332% 5,353/1,611,764 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.2%	83
European (non-Finnish)grpmax	0.37%	270
Remaining individualsnot grpmax-eligible	0.223%	449
Ashkenazi Jewishnot grpmax-eligible	0.149%	671
African / African-American	0.032%	3,125
Admixed American	0.0218%	4,589
Middle Eastern	0.0165%	6,060
South Asian	0.0011%	90,498

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys718Phe
Coding: c.2153G>T
MANE Select: NM_001080449
dbSNP: rs147096750
Type: single nucleotide variant
Location: chr10:68430491 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB
Residue 718: the upf1-type sf1b helicase atp-binding domain; the 'helicase activity' region

Full DNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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DNA2 c.2402+1G>A Uncertain significance ★★ same type
DNA2 c.257+3A>G Uncertain significance ★★ same type
DNA2 p.Ala1003Ser Uncertain significance ★★ ⚠ same type
DNA2 p.Ala221Glu Uncertain significance ★★ ⚠ same type
DNA2 p.Ala346Val Uncertain significance ★★ ⚠ same type
DNA2 p.Ala51Val Uncertain significance ★★ ⚠ same type

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-cys718phe (accessed [today's date]).

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