Is VGF p.Pro494His (c.1481C>A) pathogenic?

VGF p.Pro494His (c.1481C>A) is classified Uncertain significance in VGF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-02). AlphaMissense: likely benign (0.1872); Very rare (popmax 0.000524%, nfe).

How common is VGF p.Pro494His (c.1481C>A) in the general population?

VGF p.Pro494His (c.1481C>A) is very rare (popmax 0.000524%, nfe) (gnomAD).

What do computational predictors say about VGF p.Pro494His (c.1481C>A)?

AlphaMissense predicts likely benign (score 0.1872) — an in-silico prediction, not a clinical call.

VGF p.Pro494His

c.1481C>A · rs1334622920 · VCV2555469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1872 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000524%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1872	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -9.10	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 6.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 445 bp · p 0.007 · regional, not allelic
Overall
CADD	23.1	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 0.000524% European (non-Finnish) · 6/1,145,060 alleles

Filtering AF 0.000188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000124%

Overall 0.000433% 6/1,386,072 alleles · very rare

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.Pro494His
Coding: c.1481C>A
MANE Select: NM_003378
dbSNP: rs1334622920
Type: single nucleotide variant
Location: chr7:101163363 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.87 · 7 PDB
Residue 494: 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-pro494his (accessed [today's date]).

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