Is VARS2 p.Pro102Ser (c.304C>T) pathogenic?

VARS2 p.Pro102Ser (c.304C>T) is classified Uncertain significance in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-19). AlphaMissense: likely benign (0.0803); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with VARS2 p.Pro102Ser (c.304C>T)?

VARS2 p.Pro102Ser (c.304C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VARS2 p.Pro102Ser (c.304C>T) in the general population?

VARS2 p.Pro102Ser (c.304C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about VARS2 p.Pro102Ser (c.304C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

VARS2 p.Pro102Ser

c.304C>T · rs773817248 · VCV2272451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -4.39	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 0.86	GERP -3.9, phastCons 0.32
Overall
CADD	17.73	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000558% 9/1,614,214 alleles · ultra-rare exomes 9/1,461,892 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000508%	196,673

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.Pro102Ser
Coding: c.304C>T
MANE Select: NM_020442
dbSNP: rs773817248
Type: single nucleotide variant
Location: chr6:30915375 (GRCh38)
Structure: AlphaFold pLDDT 88.12
Residue 102: the gst c-terminal domain

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.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
VARS1 p.Arg571Trp 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-pro102ser (accessed [today's date]).

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