Is VSX2 p.Ser259= (c.777G>A) pathogenic?

VSX2 p.Ser259= (c.777G>A) is classified Conflicting classifications of pathogenicity in VSX2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-09-21). Very rare (popmax 0.00417%, nfe); Associated with isolated microphthalmia 2.

What condition is associated with VSX2 p.Ser259= (c.777G>A)?

VSX2 p.Ser259= (c.777G>A) is associated with isolated microphthalmia 2, microphthalmia, isolated, with coloboma 3 (ClinVar).

How common is VSX2 p.Ser259= (c.777G>A) in the general population?

VSX2 p.Ser259= (c.777G>A) is very rare (popmax 0.00417%, nfe) (gnomAD).

VSX2 p.Ser259=

c.777G>A · rs371707151 · VCV314197

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00417%, nfe)

Conditions

isolated microphthalmia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.013, phastCons 1
Overall
CADD	13.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00417% European (non-Finnish) · 49/1,175,778 alleles

Filtering AF 0.00319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00337% 54/1,603,544 alleles · very rare exomes 49/1,451,318 · genomes 5/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00417%	23,995
African / African-American	0.00267%	37,426
Admixed American	0.00171%	58,510
Finnishnot grpmax-eligible	0.00159%	62,846
South Asian	0.00113%	88,742

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.Ser259=
Coding: c.777G>A
MANE Select: NM_182894
dbSNP: rs371707151
Type: single nucleotide variant
Location: chr14:74260610 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.65
Residue 259: the cvc domain

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.Ser259Pro 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
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-ser259 (accessed [today's date]).

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