Is VGF p.Pro545Arg (c.1634C>G) pathogenic?

VGF p.Pro545Arg (c.1634C>G) is classified Uncertain significance in VGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: ambiguous (0.342); Ultra-rare (popmax 0.0143%, eas).

How common is VGF p.Pro545Arg (c.1634C>G) in the general population?

VGF p.Pro545Arg (c.1634C>G) is ultra-rare (popmax 0.0143%, eas) (gnomAD).

What do computational predictors say about VGF p.Pro545Arg (c.1634C>G)?

AlphaMissense predicts ambiguous (score 0.342) — an in-silico prediction, not a clinical call.

VGF p.Pro545Arg

c.1634C>G · VCV3814935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.342 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.342	ambiguous
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.52	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 445 bp · p 0.007 · regional, not allelic
Overall
CADD	24.3	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 0.0143% East Asian · 6/42,028 alleles

Filtering AF 0.00621% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00415%

Overall 0.000388% 6/1,546,050 alleles · ultra-rare exomes 5/1,394,414 · genomes 1/151,636 · 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: VGF
Protein: p.Pro545Arg
Coding: c.1634C>G
MANE Select: NM_003378
Type: single nucleotide variant
Location: chr7:101163210 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.87 · 7 PDB
Residue 545: the 'disordered' region

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

Similar variants

VGF p.Arg308= Benign ★★ same type
VGF p.Glu107Gln Benign ★★ same type
VGF p.Leu327= Benign ★★ same type
VGF p.Pro492= Benign/Likely benign ★★ same type
VGF p.Ala149Val Uncertain significance ★ ⚠ same type
VGF p.Ala160Glu Uncertain significance ★ ⚠ same type
VGF p.Ala181Glu Uncertain significance ★ ⚠ same type
VGF p.Ala233Glu Uncertain significance ★ ⚠ 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/vgf-p-pro545arg (accessed [today's date]).

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