Is VARS2 p.Pro876fs (c.2627del) pathogenic?

VARS2 p.Pro876fs (c.2627del) is classified Likely pathogenic in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-18). Very rare (popmax 0.000172%, nfe); Associated with VARS2-related disorder.

What condition is associated with VARS2 p.Pro876fs (c.2627del)?

VARS2 p.Pro876fs (c.2627del) is associated with VARS2-related disorder (ClinVar).

How common is VARS2 p.Pro876fs (c.2627del) in the general population?

VARS2 p.Pro876fs (c.2627del) is very rare (popmax 0.000172%, nfe) (gnomAD).

VARS2 p.Pro876fs

c.2627del · VCV4974068

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000172%, nfe)

Conditions

VARS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.58	GERP -1.8

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000172% European (non-Finnish) · 2/1,162,314 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,587,324 alleles · very rare exomes 2/1,435,114 · genomes 0/152,210 · 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: VARS2
Protein: p.Pro876fs
Coding: c.2627del
MANE Select: NM_020442
Type: Deletion
Location: chr6:30924509 (GRCh38)
Structure: AlphaFold pLDDT 88.12

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

Disease context

VARS2-related disorder

Similar variants

VARS1 p.Val876Ile Uncertain significance ★ ⚠ same residue
VARS2 p.Val495Gly Uncertain significance ★★ ⚠ same condition
VARS1 p.Gln126Ter Likely pathogenic ★ same condition
VARS2 p.Arg171Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
VARS2 p.Arg439Trp Uncertain significance ★ same condition
VARS2 p.Arg490Ter Conflicting classifications of pathogenicity ★ same condition
VARS1 c.2348-8TC[2] Likely benign same condition
VARS1 p.Ala74= Likely benign 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-pro876fs (accessed [today's date]).

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