Is DARS2 p.Ser59Leu (c.176C>T) pathogenic?

DARS2 p.Ser59Leu (c.176C>T) is classified Uncertain significance in DARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-11). AlphaMissense: likely benign (0.0796); Very rare (popmax 0.0033%, sas); Associated with Inborn genetic diseases.

What condition is associated with DARS2 p.Ser59Leu (c.176C>T)?

DARS2 p.Ser59Leu (c.176C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DARS2 p.Ser59Leu (c.176C>T) in the general population?

DARS2 p.Ser59Leu (c.176C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about DARS2 p.Ser59Leu (c.176C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

DARS2 p.Ser59Leu

c.176C>T · rs766857338 · VCV2251252

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -6.45	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	23.5	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 0.0033% South Asian · 3/90,992 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00112% 18/1,609,628 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,331
Admixed American	0.00168%	59,426
Remaining individualsnot grpmax-eligible	0.0016%	62,398
European (non-Finnish)	0.0011%	90,714

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.Ser59Leu
Coding: c.176C>T
MANE Select: NM_018122
dbSNP: rs766857338
Type: single nucleotide variant
Location: chr1:173826735 (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.Leu201Phe Uncertain significance ★★ ⚠ same condition
DARS2 p.Leu204Val 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-ser59leu (accessed [today's date]).

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