Is VSX2 p.Arg347Ser (c.1041G>T) pathogenic?

VSX2 p.Arg347Ser (c.1041G>T) is classified Uncertain significance in VSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely benign (0.1457); Ultra-rare (popmax 0.0113%, amr); Associated with Inborn genetic diseases.

What condition is associated with VSX2 p.Arg347Ser (c.1041G>T)?

VSX2 p.Arg347Ser (c.1041G>T) is associated with Inborn genetic diseases (ClinVar).

How common is VSX2 p.Arg347Ser (c.1041G>T) in the general population?

VSX2 p.Arg347Ser (c.1041G>T) is ultra-rare (popmax 0.0113%, amr) (gnomAD).

What do computational predictors say about VSX2 p.Arg347Ser (c.1041G>T)?

AlphaMissense predicts likely benign (score 0.1457) — an in-silico prediction, not a clinical call.

VSX2 p.Arg347Ser

c.1041G>T · VCV3332383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1457 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1457	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -5.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.43 · regional, not allelic
Overall
CADD	18.79	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 0.0113% Admixed American · 6/53,040 alleles

Filtering AF 0.00485% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00336%

Overall 0.000424% 6/1,415,058 alleles · ultra-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: VSX2
Protein: p.Arg347Ser
Coding: c.1041G>T
MANE Select: NM_182894
Type: single nucleotide variant
Location: chr14:74260874 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.65
Residue 347: the 'disordered' region

Full VSX2 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

VSX2 p.Arg199His Uncertain significance ★★ ⚠ same condition
VSX2 p.Arg206Gln Uncertain significance ★★ ⚠ same condition
VSX2 p.Arg274His Uncertain significance ★★ ⚠ same condition
VSX2 p.Arg288Gln Uncertain significance ★★ ⚠ same condition
VSX2 p.Arg332Trp Uncertain significance ★★ ⚠ same condition
VSX2 p.Pro45Leu Uncertain significance ★★ ⚠ same condition
VSX2 p.Ala294Val Uncertain significance ★ ⚠ same condition
VSX2 p.Ala313Val 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/vsx2-p-arg347ser (accessed [today's date]).

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