Is VSX2 p.Arg200Pro (c.599G>C) pathogenic?

VSX2 p.Arg200Pro (c.599G>C) is classified Pathogenic/Likely pathogenic in VSX2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-01-16). AlphaMissense: likely pathogenic (0.9998); Rare (popmax 0.116%, mid); Associated with isolated microphthalmia 2.

What condition is associated with VSX2 p.Arg200Pro (c.599G>C)?

VSX2 p.Arg200Pro (c.599G>C) is associated with isolated microphthalmia 2, microphthalmia, isolated, with coloboma 3 (ClinVar).

How common is VSX2 p.Arg200Pro (c.599G>C) in the general population?

VSX2 p.Arg200Pro (c.599G>C) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about VSX2 p.Arg200Pro (c.599G>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

VSX2 p.Arg200Pro

c.599G>C · rs121912543 · VCV14861

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated microphthalmia 2

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 8% in VSX2
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -16.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.43 · regional, not allelic
Overall
CADD	34.0	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 0.116% Middle Eastern · 7/6,060 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.000479% 7/1,461,872 alleles · 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.Arg200Pro
Coding: c.599G>C
MANE Select: NM_182894
dbSNP: rs121912543
Type: single nucleotide variant
Location: chr14:74259621 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.65
Residue 200: a UniProt-annotated variant site (in mcopcti; loss of dna binding capacity); a UniProt-annotated variant site (in mcopcti; loss of dna binding capacity at consensus sequences; abnormal and prolonged expression of mitf and wls; mislocalization of ctnnb1); a DNA-binding region

Full VSX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

isolated microphthalmia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microphthalmia, isolated, with coloboma 3

Similar variants

VSX2 p.Arg200Gln Pathogenic ★★ same residue
VSX2 p.Arg200Ter Pathogenic ★★ same residue
VSX2 p.Arg200= Likely benign ★ same residue
VSX2 c.371-1G>A Pathogenic ★★ same condition
VSX2 p.Arg227Trp Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Cys29Ter Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Gln197Ter Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Trp195Ter Pathogenic/Likely pathogenic ★★ 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-arg200pro (accessed [today's date]).

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