Is GARS1 p.Pro499Ser (c.1495C>T) pathogenic?

GARS1 p.Pro499Ser (c.1495C>T) is classified Uncertain significance in GARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-15). AlphaMissense: likely benign (0.2069); Very rare (popmax 0.0011%, sas).

How common is GARS1 p.Pro499Ser (c.1495C>T) in the general population?

GARS1 p.Pro499Ser (c.1495C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about GARS1 p.Pro499Ser (c.1495C>T)?

AlphaMissense predicts likely benign (score 0.2069) — an in-silico prediction, not a clinical call.

GARS1 p.Pro499Ser

c.1495C>T · rs1428449193 · VCV1320886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2069	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -12.24	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.95, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 34 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	23.8	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 0.0011% South Asian · 1/91,082 alleles

Overall 0.000124% 2/1,614,086 alleles · very rare exomes 2/1,461,822 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,004

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.Pro499Ser
Coding: c.1495C>T
MANE Select: NM_002047
dbSNP: rs1428449193
Type: single nucleotide variant
Location: chr7:30622344 (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.Pro499= Likely benign ★ same residue
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

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-pro499ser (accessed [today's date]).

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