Is GARS1 p.Arg34Trp (c.100C>T) pathogenic?

GARS1 p.Arg34Trp (c.100C>T) is classified Uncertain significance in GARS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-19). AlphaMissense: ambiguous (0.3543); Ultra-rare (popmax 0.0188%, afr).

How common is GARS1 p.Arg34Trp (c.100C>T) in the general population?

GARS1 p.Arg34Trp (c.100C>T) is ultra-rare (popmax 0.0188%, afr) (gnomAD).

What do computational predictors say about GARS1 p.Arg34Trp (c.100C>T)?

AlphaMissense predicts ambiguous (score 0.3543) — an in-silico prediction, not a clinical call.

GARS1 p.Arg34Trp

c.100C>T · rs928410877 · VCV1698077

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3543 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3543	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.26, phastCons 0.84
Regional constraint	o/e 1.12	unconstrained · MANE · 5,108 bp · p 0.097 · regional, not allelic
Overall
CADD	20.7	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 0.0188% African / African-American · 14/74,540 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00909%

Overall 0.00095% 15/1,579,294 alleles · ultra-rare exomes 7/1,427,078 · genomes 8/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0188%	5,324
Admixed American	0.00174%	57,622

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.Arg34Trp
Coding: c.100C>T
MANE Select: NM_002047
dbSNP: rs928410877
Type: single nucleotide variant
Location: chr7:30595021 (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.Arg34Gln Uncertain significance ★★ ⚠ same residue
GARS1 p.Arg34Leu Uncertain significance ★ ⚠ 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

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-arg34trp (accessed [today's date]).

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