Is DARS2 p.Asp461Glu (c.1383C>A) pathogenic?

DARS2 p.Asp461Glu (c.1383C>A) is classified Uncertain significance in DARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: likely benign (0.1832); Ultra-rare (popmax 0.0331%, mid).

How common is DARS2 p.Asp461Glu (c.1383C>A) in the general population?

DARS2 p.Asp461Glu (c.1383C>A) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about DARS2 p.Asp461Glu (c.1383C>A)?

AlphaMissense predicts likely benign (score 0.1832) — an in-silico prediction, not a clinical call.

DARS2 p.Asp461Glu

c.1383C>A · rs1653747062 · VCV1496726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1832	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -0.37, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	13.31	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 0.0331% Middle Eastern · 2/6,034 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000372% 6/1,613,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,017
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-American	0.00134%	74,888
European (non-Finnish)	8.47e-05%	1,180,034

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: DARS2
Protein: p.Asp461Glu
Coding: c.1383C>A
MANE Select: NM_018122
dbSNP: rs1653747062
Type: single nucleotide variant
Location: chr1:173853387 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.91 · 1 PDB

Full DARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DARS2 p.Asp461Tyr Uncertain significance ★★ ⚠ same residue
DARS2 c.228-15C>A Pathogenic/Likely pathogenic ★★ same type
DARS2 c.228-16C>A Pathogenic/Likely pathogenic ★★ same type
DARS2 c.397-2A>G Pathogenic/Likely pathogenic ★★ same type
DARS2 c.492+2T>C Pathogenic ★★ same type
DARS2 c.493-1G>C Likely pathogenic ★★ same type
DARS2 p.Ala262Val Likely pathogenic ★★ ⚠ same type
DARS2 p.Arg179His Pathogenic/Likely pathogenic ★★ 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/dars2-p-asp461glu (accessed [today's date]).

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