Is VSX2 p.Ser157Phe (c.470C>T) pathogenic?

VSX2 p.Ser157Phe (c.470C>T) is classified Uncertain significance in VSX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-17). AlphaMissense: likely pathogenic (0.9873); Very rare (popmax 0.0022%, sas); Associated with microphthalmia.

What condition is associated with VSX2 p.Ser157Phe (c.470C>T)?

VSX2 p.Ser157Phe (c.470C>T) is associated with microphthalmia (ClinVar).

How common is VSX2 p.Ser157Phe (c.470C>T) in the general population?

VSX2 p.Ser157Phe (c.470C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about VSX2 p.Ser157Phe (c.470C>T)?

AlphaMissense predicts likely pathogenic (score 0.9873) — an in-silico prediction, not a clinical call.

VSX2 p.Ser157Phe

c.470C>T · rs551394732 · VCV989730

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microphthalmia

Computational evidence

Protein change
AlphaMissense	0.9873	likely pathogenic
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -13.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 2.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.43 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,040 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,613,686 alleles · very rare exomes 2/1,461,776 · genomes 1/151,910 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,520
Admixed American	0.00167%	59,982

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.Ser157Phe
Coding: c.470C>T
MANE Select: NM_182894
dbSNP: rs551394732
Type: single nucleotide variant
Location: chr14:74245179 (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

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

Similar variants

VSX2 p.Ser157= Benign ★★ same residue
VSX2 c.371-1G>A Pathogenic ★★ same condition
VSX2 p.Arg200Gln Pathogenic ★★ same condition
VSX2 p.Arg200Ter Pathogenic ★★ same condition
VSX2 p.Arg227Trp Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Gln197Ter Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Trp195Ter Pathogenic/Likely pathogenic ★★ same condition
VSX2 p.Asp174= Benign/Likely benign ★★ 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-ser157phe (accessed [today's date]).

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