Is DARS2 p.Ala554Thr (c.1660G>A) pathogenic?

DARS2 p.Ala554Thr (c.1660G>A) is classified Uncertain significance in DARS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-03). AlphaMissense: likely benign (0.0705); Ultra-rare (popmax 0.0167%, amr); Associated with Inborn genetic diseases.

What condition is associated with DARS2 p.Ala554Thr (c.1660G>A)?

DARS2 p.Ala554Thr (c.1660G>A) is associated with Inborn genetic diseases, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (ClinVar).

How common is DARS2 p.Ala554Thr (c.1660G>A) in the general population?

DARS2 p.Ala554Thr (c.1660G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about DARS2 p.Ala554Thr (c.1660G>A)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

DARS2 p.Ala554Thr

c.1660G>A · rs147603024 · VCV1510912

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.02	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 4.8	GERP -2.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	16.99	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 0.0167% Admixed American · 10/59,998 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00297% 48/1,613,554 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00401%	24,965
European (non-Finnish)	0.00246%	40,677

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.Ala554Thr
Coding: c.1660G>A
MANE Select: NM_018122
dbSNP: rs147603024
Type: single nucleotide variant
Location: chr1:173853891 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Similar variants

DARS2 c.228-15C>A Pathogenic/Likely pathogenic ★★ same condition
DARS2 c.228-16C>A Pathogenic/Likely pathogenic ★★ same condition
DARS2 c.397-2A>G Pathogenic/Likely pathogenic ★★ same condition
DARS2 c.492+2T>C Pathogenic ★★ same condition
DARS2 c.493-1G>C Likely pathogenic ★★ same condition
DARS2 p.Ala262Val Likely pathogenic ★★ same condition
DARS2 p.Arg179His Pathogenic/Likely pathogenic ★★ same condition
DARS2 p.Arg188Ter Pathogenic/Likely pathogenic ★★ same condition

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-ala554thr (accessed [today's date]).

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