Is VSX2 p.Asp291= (c.873C>T) pathogenic?

VSX2 p.Asp291= (c.873C>T) is classified Likely benign in VSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). Ultra-rare (popmax 0.0476%, eas); Associated with isolated microphthalmia 2.

What condition is associated with VSX2 p.Asp291= (c.873C>T)?

VSX2 p.Asp291= (c.873C>T) is associated with isolated microphthalmia 2 (ClinVar).

How common is VSX2 p.Asp291= (c.873C>T) in the general population?

VSX2 p.Asp291= (c.873C>T) is ultra-rare (popmax 0.0476%, eas) (gnomAD).

VSX2 p.Asp291=

c.873C>T · rs146821562 · VCV1108865

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0476%, eas)

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 -2.2	GERP -3.7
Overall
CADD	7.691	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0476% East Asian · 21/44,138 alleles

Filtering AF 0.0318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0268%

Overall 0.00314% 50/1,593,748 alleles · ultra-rare exomes 44/1,441,416 · genomes 6/152,332 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0476%	2,102
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,112
Remaining individualsnot grpmax-eligible	0.00324%	30,869
South Asian	0.00228%	43,877
European (non-Finnish)	0.00196%	50,896
Admixed American	0.00177%	56,530

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.Asp291=
Coding: c.873C>T
MANE Select: NM_182894
dbSNP: rs146821562
Type: single nucleotide variant
Location: chr14:74260706 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.65
Residue 291: 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.Asp291Asn Benign ★★ 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
VSX2 p.Cys29Ter Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Gln197Ter 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-asp291 (accessed [today's date]).

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