Is VARS2 p.Ala321Pro (c.961G>C) pathogenic?

VARS2 p.Ala321Pro (c.961G>C) is classified Uncertain significance in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: likely pathogenic (0.8674); Absent from gnomAD v4.1.

How common is VARS2 p.Ala321Pro (c.961G>C) in the general population?

VARS2 p.Ala321Pro (c.961G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VARS2 p.Ala321Pro (c.961G>C)?

AlphaMissense predicts likely pathogenic (score 0.8674) — an in-silico prediction, not a clinical call.

VARS2 p.Ala321Pro

c.961G>C · rs2538640348 · VCV2003333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8674 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8674	likely pathogenic
REVEL	0.382	indeterminate
SaProt	LLR -13.89	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2, phastCons 1
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VARS2
Protein: p.Ala321Pro
Coding: c.961G>C
MANE Select: NM_020442
dbSNP: rs2538640348
Type: single nucleotide variant
Location: chr6:30917782 (GRCh38)
Structure: AlphaFold pLDDT 88.12

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

Similar variants

VARS1 p.Arg1058Gln Likely pathogenic ★★ ⚠ same type
VARS1 p.Arg1119Cys Pathogenic/Likely pathogenic ★★ same type
VARS1 p.Arg1208Ter Pathogenic/Likely pathogenic ★★ same type
VARS1 p.Gln1039Ter Likely pathogenic ★★ same type
VARS1 p.Trp790Ter Pathogenic/Likely pathogenic ★★ same type
VARS2 c.1480-2A>G Likely pathogenic ★★ same type
VARS2 c.2467-2A>G Pathogenic/Likely pathogenic ★★ same type
VARS2 p.Arg1002Ter 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/vars2-p-ala321pro (accessed [today's date]).

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