Is DARS2 p.Thr136Ala (c.406A>G) pathogenic?

DARS2 p.Thr136Ala (c.406A>G) is classified Uncertain significance in DARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: ambiguous (0.3732); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with DARS2 p.Thr136Ala (c.406A>G)?

DARS2 p.Thr136Ala (c.406A>G) is associated with Inborn genetic diseases (ClinVar).

How common is DARS2 p.Thr136Ala (c.406A>G) in the general population?

DARS2 p.Thr136Ala (c.406A>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about DARS2 p.Thr136Ala (c.406A>G)?

AlphaMissense predicts ambiguous (score 0.3732) — an in-silico prediction, not a clinical call.

DARS2 p.Thr136Ala

c.406A>G · VCV3270893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3732	ambiguous
REVEL	0.73	pathogenic-leaning
SaProt	LLR -11.35	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.35	acceptor loss, 4 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	29.8	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 0.00329% South Asian · 3/91,064 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000547% 8/1,461,404 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,355
Remaining individualsnot grpmax-eligible	0.0016%	62,502
Finnishnot grpmax-eligible	0.00156%	64,044
European (non-Finnish)	0.000254%	393,216

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.Thr136Ala
Coding: c.406A>G
MANE Select: NM_018122
Type: single nucleotide variant
Location: chr1:173831544 (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

Similar variants

DARS2 p.Thr136Ser Uncertain significance ★★ ⚠ same residue
DARS2 p.Thr136Lys Uncertain significance ★ ⚠ same residue
DARS2 p.Arg58Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
DARS2 p.Ala554Thr Uncertain significance ★★ ⚠ same condition
DARS2 p.Arg31Gly Uncertain significance ★★ ⚠ same condition
DARS2 p.Arg381Met Uncertain significance ★★ ⚠ same condition
DARS2 p.Asn416Asp Uncertain significance ★★ ⚠ same condition
DARS2 p.Cys590Arg Uncertain significance ★★ ⚠ 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-thr136ala (accessed [today's date]).

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