Is DARS1 p.Pro496Ala (c.1486C>G) pathogenic?

DARS1 p.Pro496Ala (c.1486C>G) is classified Uncertain significance in DARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.9229); Ultra-rare (popmax 0.0522%, amr).

How common is DARS1 p.Pro496Ala (c.1486C>G) in the general population?

DARS1 p.Pro496Ala (c.1486C>G) is ultra-rare (popmax 0.0522%, amr) (gnomAD).

What do computational predictors say about DARS1 p.Pro496Ala (c.1486C>G)?

AlphaMissense predicts likely pathogenic (score 0.9229) — an in-silico prediction, not a clinical call.

DARS1 p.Pro496Ala

c.1486C>G · rs1020492946 · VCV2124048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9229 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0522%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9229	likely pathogenic
REVEL	0.639	indeterminate
SaProt	LLR -12.59	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 78 kb · p 0.69 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0522% Admixed American · 31/59,420 alleles

Filtering AF 0.0377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0328%

Overall 0.00193% 31/1,605,218 alleles · ultra-rare

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.Pro496Ala
Coding: c.1486C>G
MANE Select: NM_001349
dbSNP: rs1020492946
Type: single nucleotide variant
Location: chr2:135907336 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 3 PDB

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-pro496ala (accessed [today's date]).

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