Is DARS2 p.Thr67Ile (c.200C>T) pathogenic?

DARS2 p.Thr67Ile (c.200C>T) is classified Uncertain significance in DARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.1258); Very rare (popmax 0.00879%, sas); Associated with Inborn genetic diseases.

What condition is associated with DARS2 p.Thr67Ile (c.200C>T)?

DARS2 p.Thr67Ile (c.200C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DARS2 p.Thr67Ile (c.200C>T) in the general population?

DARS2 p.Thr67Ile (c.200C>T) is very rare (popmax 0.00879%, sas) (gnomAD).

What do computational predictors say about DARS2 p.Thr67Ile (c.200C>T)?

AlphaMissense predicts likely benign (score 0.1258) — an in-silico prediction, not a clinical call.

DARS2 p.Thr67Ile

c.200C>T · VCV4237630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00879%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1258	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -8.40	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 2.7	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	24.2	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 0.00879% South Asian · 8/91,060 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00062% 10/1,613,140 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00879%	11,382
East Asian	0.00223%	44,868
African / African-American	0.00134%	74,762

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.Thr67Ile
Coding: c.200C>T
MANE Select: NM_018122
Type: single nucleotide variant
Location: chr1:173826759 (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.Thr67Asn Uncertain significance ★ ⚠ same residue
DARS2 p.Thr67= Likely benign ★ 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-thr67ile (accessed [today's date]).

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