Is VARS2 p.Ser355Pro (c.1063T>C) pathogenic?

VARS2 p.Ser355Pro (c.1063T>C) is classified Uncertain significance in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely benign (0.0527); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with VARS2 p.Ser355Pro (c.1063T>C)?

VARS2 p.Ser355Pro (c.1063T>C) is associated with Inborn genetic diseases (ClinVar).

How common is VARS2 p.Ser355Pro (c.1063T>C) in the general population?

VARS2 p.Ser355Pro (c.1063T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about VARS2 p.Ser355Pro (c.1063T>C)?

AlphaMissense predicts likely benign (score 0.0527) — an in-silico prediction, not a clinical call.

VARS2 p.Ser355Pro

c.1063T>C · rs1485283019 · VCV2486896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0527	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.85	GERP -2.9
Overall
CADD	1.217	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,612,838 alleles · very rare exomes 3/1,460,550 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
European (non-Finnish)	8.47e-05%	1,180,025

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.Ser355Pro
Coding: c.1063T>C
MANE Select: NM_020442
dbSNP: rs1485283019
Type: single nucleotide variant
Location: chr6:30918904 (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.Ser355Leu Uncertain significance ★ ⚠ same residue
VARS2 p.Ser355= Benign/Likely benign ★★ 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

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-ser355pro (accessed [today's date]).

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