Is VARS2 p.Arg554Trp (c.1660C>T) pathogenic?

VARS2 p.Arg554Trp (c.1660C>T) is classified Uncertain significance in VARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-08). AlphaMissense: likely benign (0.118); Very rare (popmax 0.00223%, sas); Associated with Inborn genetic diseases.

What condition is associated with VARS2 p.Arg554Trp (c.1660C>T)?

VARS2 p.Arg554Trp (c.1660C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VARS2 p.Arg554Trp (c.1660C>T) in the general population?

VARS2 p.Arg554Trp (c.1660C>T) is very rare (popmax 0.00223%, sas) (gnomAD).

What do computational predictors say about VARS2 p.Arg554Trp (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.118) — an in-silico prediction, not a clinical call.

VARS2 p.Arg554Trp

c.1660C>T · rs377324441 · VCV445977

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.118	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -13.84	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.1	GERP -2.9
Overall
CADD	23.0	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 0.00223% South Asian · 2/89,644 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000871% 14/1,608,084 alleles · very rare exomes 13/1,455,970 · genomes 1/152,114 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00223%	44,822
Remaining individualsnot grpmax-eligible	0.0016%	62,326
European (non-Finnish)	0.000933%	107,152

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: VARS2
Protein: p.Arg554Trp
Coding: c.1660C>T
MANE Select: NM_020442
dbSNP: rs377324441
Type: single nucleotide variant
Location: chr6:30921616 (GRCh38)
Structure: AlphaFold pLDDT 88.12

Full VARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VARS2 p.Arg554Gln Uncertain significance ★★ ⚠ same residue
VARS2 p.Arg1002Ter Pathogenic ★★ same condition
VARS2 p.Glu486Ter Pathogenic/Likely pathogenic ★★ same condition
VARS2 p.Thr337Ile Pathogenic ★★ same condition
VARS1 p.Ala595Thr Uncertain significance ★★ ⚠ same condition
VARS1 p.Arg371His Uncertain significance ★★ ⚠ same condition
VARS1 p.Arg473His Uncertain significance ★★ ⚠ same condition
VARS1 p.Arg537Gln Uncertain significance ★★ ⚠ same condition

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/vars2-p-arg554trp (accessed [today's date]).

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