Is DARS2 p.Leu201Phe (c.601C>T) pathogenic?

DARS2 p.Leu201Phe (c.601C>T) is classified Uncertain significance in DARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.3829); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DARS2 p.Leu201Phe (c.601C>T)?

DARS2 p.Leu201Phe (c.601C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DARS2 p.Leu201Phe (c.601C>T) in the general population?

DARS2 p.Leu201Phe (c.601C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DARS2 p.Leu201Phe (c.601C>T)?

AlphaMissense predicts ambiguous (score 0.3829) — an in-silico prediction, not a clinical call.

DARS2 p.Leu201Phe

c.601C>T · VCV3380196

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3829	ambiguous
REVEL	0.684	pathogenic-leaning
SaProt	LLR -12.95	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	28.2	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 0.000339% European (non-Finnish) · 4/1,180,030 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)grpmax	0.000339%	295,008

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu201Phe
Coding: c.601C>T
MANE Select: NM_018122
Type: single nucleotide variant
Location: chr1:173833484 (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.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
DARS2 p.Leu204Val Uncertain significance ★★ ⚠ same condition
DARS2 p.Met419Val 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-leu201phe (accessed [today's date]).

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