Is VAC14 p.Pro433Arg (c.1298C>G) pathogenic?

VAC14 p.Pro433Arg (c.1298C>G) is classified Uncertain significance in VAC14 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-27). AlphaMissense: likely pathogenic (0.9548); Absent from gnomAD v4.1.

How common is VAC14 p.Pro433Arg (c.1298C>G) in the general population?

VAC14 p.Pro433Arg (c.1298C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VAC14 p.Pro433Arg (c.1298C>G)?

AlphaMissense predicts likely pathogenic (score 0.9548) — an in-silico prediction, not a clinical call.

VAC14 p.Pro433Arg

c.1298C>G · rs2507658252 · VCV2118350

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9548 · 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	0.9548	likely pathogenic
REVEL	0.52	indeterminate
SaProt	LLR -14.78	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 69 kb · p 0.0052 · regional, not allelic
Overall
CADD	31.0	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: VAC14
Protein: p.Pro433Arg
Coding: c.1298C>G
MANE Select: NM_018052
dbSNP: rs2507658252
Type: single nucleotide variant
Location: chr16:70762888 (GRCh38)
Gene constraint: LOEUF 0.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.63 · 1 PDB

Full VAC14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VAC14 p.Leu308Ter Pathogenic/Likely pathogenic ★★ same type
VAC14 p.Ala474Thr Uncertain significance ★★ ⚠ same type
VAC14 p.Arg110His Uncertain significance ★★ ⚠ same type
VAC14 p.Arg434Trp Uncertain significance ★★ same type
VAC14 p.Arg438Gln Uncertain significance ★★ ⚠ same type
VAC14 p.Arg438Trp Uncertain significance ★★ ⚠ same type
VAC14 p.Arg623Cys Uncertain significance ★★ ⚠ same type
VAC14 p.Arg766Gln 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/vac14-p-pro433arg (accessed [today's date]).

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