Is DARS1 p.Arg441fs (c.1323_1324del) pathogenic?

DARS1 p.Arg441fs (c.13231324del) is classified Uncertain significance in DARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). Very rare (popmax 0.00256%, sas).

How common is DARS1 p.Arg441fs (c.1323_1324del) in the general population?

DARS1 p.Arg441fs (c.1323_1324del) is very rare (popmax 0.00256%, sas) (gnomAD).

DARS1 p.Arg441fs

c.1323_1324del · rs768678855 · VCV1682546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00256%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00256% South Asian · 2/78,100 alleles

Filtering AF 0.000425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000617% 6/972,594 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00256%	39,050
European (non-Finnish)	0.000673%	148,554

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: DARS1
Protein: p.Arg441fs
Coding: c.1323_1324del
MANE Select: NM_001349
dbSNP: rs768678855
Type: Microsatellite
Location: chr2:135911400 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 3 PDB
Residue 441: an α-helix

Full DARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DARS1 p.4AS[3] Likely benign ★★ same type
DARS1 c.505-18_505-14del Likely benign ★ 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/dars1-p-arg441fs (accessed [today's date]).

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