Is VSX2 p.Arg274= (c.822C>G) pathogenic?

VSX2 p.Arg274= (c.822C>G) is classified Likely benign in VSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). Ultra-rare (popmax 0.0135%, sas); Associated with isolated microphthalmia 2.

What condition is associated with VSX2 p.Arg274= (c.822C>G)?

VSX2 p.Arg274= (c.822C>G) is associated with isolated microphthalmia 2 (ClinVar).

How common is VSX2 p.Arg274= (c.822C>G) in the general population?

VSX2 p.Arg274= (c.822C>G) is ultra-rare (popmax 0.0135%, sas) (gnomAD).

VSX2 p.Arg274=

c.822C>G · rs756475048 · VCV1088758

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, sas)

Conditions

isolated microphthalmia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -1.1, phastCons 1
Overall
CADD	8.766	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0135% South Asian · 12/88,838 alleles

Filtering AF 0.00778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00607%

Overall 0.000998% 16/1,603,398 alleles · ultra-rare exomes 16/1,451,056 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0135%	7,403
East Asian	0.00225%	44,456
Remaining individualsnot grpmax-eligible	0.00161%	62,020
European (non-Finnish)	0.00017%	587,838

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.Arg274=
Coding: c.822C>G
MANE Select: NM_182894
dbSNP: rs756475048
Type: single nucleotide variant
Location: chr14:74260655 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.65
Residue 274: the 'disordered' 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

Similar variants

VSX2 p.Arg274His Uncertain significance ★★ ⚠ same residue
VSX2 p.Arg274Cys Uncertain significance ★ ⚠ same residue
VSX2 p.Arg274Gly Uncertain significance ★ ⚠ same residue
VSX2 c.371-1G>A Pathogenic ★★ same condition
VSX2 p.Arg200Gln Pathogenic ★★ same condition
VSX2 p.Arg200Pro Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Arg200Ter Pathogenic ★★ same condition
VSX2 p.Arg227Trp 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-arg274 (accessed [today's date]).

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