Is DARS1 p.Pro464Leu (c.1391C>T) pathogenic?

DARS1 p.Pro464Leu (c.1391C>T) is classified Conflicting classifications of pathogenicity in DARS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.2655); Rare (popmax 0.161%, afr).

How common is DARS1 p.Pro464Leu (c.1391C>T) in the general population?

DARS1 p.Pro464Leu (c.1391C>T) is rare (popmax 0.161%, afr) (gnomAD).

What do computational predictors say about DARS1 p.Pro464Leu (c.1391C>T)?

AlphaMissense predicts likely benign (score 0.2655) — an in-silico prediction, not a clinical call.

DARS1 p.Pro464Leu

c.1391C>T · rs148806569 · VCV1008335

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2655 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.161%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2655	likely benign
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -13.40	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 78 kb · p 0.69 · regional, not allelic
Overall
CADD	32.0	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 0.161% African / African-American · 118/73,218 alleles

Filtering AF 0.138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.129%

Overall 0.0085% 130/1,530,152 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.161%	620
Remaining individualsnot grpmax-eligible	0.00671%	14,909
Admixed American	0.00669%	14,954
European (non-Finnish)	0.000362%	275,991

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: DARS1
Protein: p.Pro464Leu
Coding: c.1391C>T
MANE Select: NM_001349
dbSNP: rs148806569
Type: single nucleotide variant
Location: chr2:135911162 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 3 PDB
Residue 464: a UniProt-annotated variant site (in hbsl)

Full DARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DARS1 p.Ala429Thr Uncertain significance ★★ ⚠ same type
DARS1 p.Arg197Cys Uncertain significance ★★ ⚠ same type
DARS1 p.Arg498Gln Uncertain significance ★★ ⚠ same type
DARS1 p.Arg63His Uncertain significance ★★ ⚠ same type
DARS1 p.Arg81His Uncertain significance ★★ ⚠ same type
DARS1 p.Asn233Ser Uncertain significance ★★ ⚠ same type
DARS1 p.Glu357Lys Uncertain significance ★★ ⚠ same type
DARS1 p.Gly170Arg Uncertain significance ★★ ⚠ 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/dars1-p-pro464leu (accessed [today's date]).

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