Is VARS2 p.Pro504Leu (c.1511C>T) pathogenic?

VARS2 p.Pro504Leu (c.1511C>T) is classified Uncertain significance in VARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-31). AlphaMissense: ambiguous (0.5211); Very rare (popmax 8.48e-05%, nfe).

How common is VARS2 p.Pro504Leu (c.1511C>T) in the general population?

VARS2 p.Pro504Leu (c.1511C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about VARS2 p.Pro504Leu (c.1511C>T)?

AlphaMissense predicts ambiguous (score 0.5211) — an in-silico prediction, not a clinical call.

VARS2 p.Pro504Leu

c.1511C>T · VCV3897331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5211 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5211	ambiguous
REVEL	0.472	indeterminate
SaProt	LLR -10.28	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Overall
CADD	25.3	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 8.48e-05% European (non-Finnish) · 1/1,179,856 alleles

Overall 6.2e-05% 1/1,613,830 alleles · very rare exomes 1/1,461,564 · genomes 0/152,266 · 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.Pro504Leu
Coding: c.1511C>T
MANE Select: NM_020442
Type: single nucleotide variant
Location: chr6:30921096 (GRCh38)
Structure: AlphaFold pLDDT 88.12

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

Similar variants

VARS2 p.Pro504= Likely benign ★ same residue
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

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-pro504leu (accessed [today's date]).

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