Is DARS1 p.Arg498Ter (c.1492C>T) pathogenic?

DARS1 p.Arg498Ter (c.1492C>T) is classified Uncertain significance in DARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-20). Very rare (popmax 0.00138%, afr).

How common is DARS1 p.Arg498Ter (c.1492C>T) in the general population?

DARS1 p.Arg498Ter (c.1492C>T) is very rare (popmax 0.00138%, afr) (gnomAD).

DARS1 p.Arg498Ter

c.1492C>T · rs763133905 · VCV1311067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, phastCons 1
Overall
CADD	39.0	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 0.00138% African / African-American · 1/72,538 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000379% 6/1,583,330 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00138%	72,538
European (non-Finnish)	0.00043%	232,725

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.Arg498Ter
Coding: c.1492C>T
MANE Select: NM_001349
dbSNP: rs763133905
Type: single nucleotide variant
Location: chr2:135907330 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 3 PDB

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

Similar variants

DARS1 p.Arg498Gln Uncertain significance ★★ ⚠ same residue
DARS1 p.Ala429Thr Uncertain significance ★★ ⚠ same type
DARS1 p.Arg197Cys Uncertain significance ★★ ⚠ same type
DARS1 p.Arg63His Uncertain significance ★★ ⚠ same type
DARS1 p.Arg81His Uncertain significance ★★ ⚠ same type
DARS1 p.Asn233Ser Uncertain significance ★★ ⚠ same type
DARS1 p.Glu357Lys Uncertain significance ★★ ⚠ same type
DARS1 p.Gly170Arg 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/dars1-p-arg498ter (accessed [today's date]).

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