Is DARS2 p.Pro126Ser (c.376C>T) pathogenic?

DARS2 p.Pro126Ser (c.376C>T) is classified Uncertain significance in DARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-02). AlphaMissense: ambiguous (0.4474); Ultra-rare (popmax 0.0294%, afr); Associated with Inborn genetic diseases.

What condition is associated with DARS2 p.Pro126Ser (c.376C>T)?

DARS2 p.Pro126Ser (c.376C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DARS2 p.Pro126Ser (c.376C>T) in the general population?

DARS2 p.Pro126Ser (c.376C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about DARS2 p.Pro126Ser (c.376C>T)?

AlphaMissense predicts ambiguous (score 0.4474) — an in-silico prediction, not a clinical call.

DARS2 p.Pro126Ser

c.376C>T · VCV3270891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4474 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4474	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -9.34	tolerated
⇒ REVEL and SaProt both call this tolerated; 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	26.9	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 0.0294% African / African-American · 22/74,924 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.0018% 29/1,613,800 alleles · ultra-rare exomes 15/1,461,606 · genomes 14/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,406
Remaining individualsnot grpmax-eligible	0.008%	12,494
South Asian	0.0011%	91,078
European (non-Finnish)	8.48e-05%	1,179,842

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.Pro126Ser
Coding: c.376C>T
MANE Select: NM_018122
Type: single nucleotide variant
Location: chr1:173830741 (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-pro126ser (accessed [today's date]).

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