Is DARS2 p.Ala448Val (c.1343C>T) pathogenic?

DARS2 p.Ala448Val (c.1343C>T) is classified Uncertain significance in DARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely benign (0.1251); Very rare (popmax 0.00333%, amr).

How common is DARS2 p.Ala448Val (c.1343C>T) in the general population?

DARS2 p.Ala448Val (c.1343C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DARS2 p.Ala448Val (c.1343C>T)?

AlphaMissense predicts likely benign (score 0.1251) — an in-silico prediction, not a clinical call.

DARS2 p.Ala448Val

c.1343C>T · rs752028936 · VCV1366980

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1251	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.30	donor gain · deltas
Pangolin	Δ0.22	loss · gain 0.09 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 0.58	GERP 1.7, phastCons 0.087
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	20.9	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 0.00333% Admixed American · 2/59,994 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000684% 10/1,461,376 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,997
European (non-Finnish)	0.000678%	147,468

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.Ala448Val
Coding: c.1343C>T
MANE Select: NM_018122
dbSNP: rs752028936
Type: single nucleotide variant
Location: chr1:173850478 (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 p.Ala448= Uncertain significance ★ same residue
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

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-ala448val (accessed [today's date]).

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