Is DARS2 p.Leu497Pro (c.1490T>C) pathogenic?

DARS2 p.Leu497Pro (c.1490T>C) is classified Uncertain significance in DARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: ambiguous (0.3954); Very rare (popmax 0.000932%, nfe).

How common is DARS2 p.Leu497Pro (c.1490T>C) in the general population?

DARS2 p.Leu497Pro (c.1490T>C) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about DARS2 p.Leu497Pro (c.1490T>C)?

AlphaMissense predicts ambiguous (score 0.3954) — an in-silico prediction, not a clinical call.

DARS2 p.Leu497Pro

c.1490T>C · VCV3392794

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3954	ambiguous
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -11.71	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	29.7	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 0.000932% European (non-Finnish) · 11/1,180,024 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000752% 11/1,461,888 alleles · very 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: DARS2
Protein: p.Leu497Pro
Coding: c.1490T>C
MANE Select: NM_018122
Type: single nucleotide variant
Location: chr1:173853494 (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-leu497pro (accessed [today's date]).

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