Is VSX2 p.Ser157= (c.471C>T) pathogenic?

VSX2 p.Ser157= (c.471C>T) is classified Benign in VSX2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 52.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with isolated microphthalmia 2.

What condition is associated with VSX2 p.Ser157= (c.471C>T)?

VSX2 p.Ser157= (c.471C>T) is associated with isolated microphthalmia 2, microphthalmia, isolated, with coloboma 3, microphthalmia (ClinVar).

VSX2 p.Ser157=

Q: How common is VSX2 p.Ser157= (c.471C>T) in the general population?

VSX2 p.Ser157= (c.471C>T) is common (popmax 52.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.471C>T · rs35435463 · VCV167840

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 52.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

isolated microphthalmia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.41	acceptor gain · deltas
Pangolin	Δ0.28	gain · loss 0.18 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.7	GERP 1.6, phastCons 1
Overall
CADD	18.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 52.3% European (non-Finnish) · 616,320/1,179,428 alleles

Filtering AF 52.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 52.1%

Overall 47.5% 766,633/1,612,744 alleles · common exomes 708,830/1,461,412 · genomes 57,803/151,332 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	65.7%	2
Finnishnot grpmax-eligible	57.2%	2
European (non-Finnish)grpmax	52.3%	2
Admixed American	48.5%	2
Remaining individualsnot grpmax-eligible	44.1%	2
Ashkenazi Jewishnot grpmax-eligible	39.2%	3
South Asian	34.3%	3
Middle Eastern	30.7%	3
African / African-American	10.9%	9
East Asian	8.58%	12

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser157=
Coding: c.471C>T
MANE Select: NM_182894
dbSNP: rs35435463
Type: single nucleotide variant
Location: chr14:74245180 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.65
Residue 157: 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 microphthalmia

Similar variants

VSX2 p.Ser157Phe 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-ser157 (accessed [today's date]).

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