Is GARS1 p.Pro489Ser (c.1465C>T) pathogenic?

GARS1 p.Pro489Ser (c.1465C>T) is classified Uncertain significance in GARS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-12). AlphaMissense: ambiguous (0.3655); Very rare (popmax 0.00017%, nfe).

How common is GARS1 p.Pro489Ser (c.1465C>T) in the general population?

GARS1 p.Pro489Ser (c.1465C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about GARS1 p.Pro489Ser (c.1465C>T)?

AlphaMissense predicts ambiguous (score 0.3655) — an in-silico prediction, not a clinical call.

GARS1 p.Pro489Ser

c.1465C>T · rs780217118 · VCV2502456

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3655	ambiguous
REVEL	0.756	pathogenic-leaning
SaProt	LLR -11.79	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 34 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	26.2	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 0.00017% European (non-Finnish) · 2/1,177,896 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,611,782 alleles · very rare exomes 2/1,459,502 · genomes 0/152,280 · joint denominator

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: GARS1
Protein: p.Pro489Ser
Coding: c.1465C>T
MANE Select: NM_002047
dbSNP: rs780217118
Type: single nucleotide variant
Location: chr7:30621498 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB

Full GARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GARS1 p.Asp200Asn Pathogenic/Likely pathogenic ★★ same type
GARS1 p.Gly294Arg Pathogenic/Likely pathogenic ★★ same type
GARS1 p.Gly339Arg Pathogenic/Likely pathogenic ★★ same type
GARS1 p.His472Arg Pathogenic ★★ same type
GARS1 p.Ile334Asn Pathogenic/Likely pathogenic ★★ same type
GARS1 p.Ile334Phe Pathogenic ★★ same type
GARS1 p.Ile334Thr Pathogenic/Likely pathogenic ★★ same type
GARS1 p.Ser265Phe 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/gars1-p-pro489ser (accessed [today's date]).

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