Is DARS2 p.Asn407Ser (c.1220A>G) pathogenic?

DARS2 p.Asn407Ser (c.1220A>G) is classified Uncertain significance in DARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.0713); Very rare (popmax 0.0033%, sas).

How common is DARS2 p.Asn407Ser (c.1220A>G) in the general population?

DARS2 p.Asn407Ser (c.1220A>G) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about DARS2 p.Asn407Ser (c.1220A>G)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

DARS2 p.Asn407Ser

c.1220A>G · rs752120872 · VCV1401669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -6.57	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 -0.55	GERP -5.1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	0.153	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 · 3/91,032 alleles

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

Overall 0.00112% 18/1,613,424 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,344
African / African-American	0.00267%	37,435
East Asian	0.00223%	44,840
Admixed American	0.00167%	59,958
Finnishnot grpmax-eligible	0.00156%	63,944
European (non-Finnish)	0.000848%	117,977

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.Asn407Ser
Coding: c.1220A>G
MANE Select: NM_018122
dbSNP: rs752120872
Type: single nucleotide variant
Location: chr1:173850355 (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

Similar variants

DARS2 c.228-15C>A Pathogenic/Likely pathogenic ★★ same type
DARS2 c.228-16C>A Pathogenic/Likely pathogenic ★★ same type
DARS2 c.397-2A>G Pathogenic/Likely pathogenic ★★ same type
DARS2 c.492+2T>C Pathogenic ★★ same type
DARS2 c.493-1G>C Likely pathogenic ★★ same type
DARS2 p.Ala262Val Likely pathogenic ★★ ⚠ same type
DARS2 p.Arg179His Pathogenic/Likely pathogenic ★★ same type
DARS2 p.Arg188Ter Pathogenic/Likely pathogenic ★★ same type

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-asn407ser (accessed [today's date]).

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