Is DARS2 p.Lys332Glu (c.994A>G) pathogenic?

DARS2 p.Lys332Glu (c.994A>G) is classified Likely pathogenic in DARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-27). AlphaMissense: likely pathogenic (0.8474); Very rare (popmax 0.00267%, afr).

How common is DARS2 p.Lys332Glu (c.994A>G) in the general population?

DARS2 p.Lys332Glu (c.994A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about DARS2 p.Lys332Glu (c.994A>G)?

AlphaMissense predicts likely pathogenic (score 0.8474) — an in-silico prediction, not a clinical call.

DARS2 p.Lys332Glu

c.994A>G · rs2525878459 · VCV1969906

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8474 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8474	likely pathogenic ✓ concordant with ClinVar
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -15.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	27.5	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 0.00267% African / African-American · 2/75,040 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,842 alleles · very rare

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.Lys332Glu
Coding: c.994A>G
MANE Select: NM_018122
dbSNP: rs2525878459
Type: single nucleotide variant
Location: chr1:173839520 (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 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
DARS2 p.Arg188Ter 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-lys332glu (accessed [today's date]).

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