Is VSX1 p.Pro247Arg (c.740C>G) pathogenic?

VSX1 p.Pro247Arg (c.740C>G) is classified Conflicting classifications of pathogenicity in VSX1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.5705); Ultra-rare (popmax 0.0647%, amr); Associated with keratoconus 1.

How common is VSX1 p.Pro247Arg (c.740C>G) in the general population?

VSX1 p.Pro247Arg (c.740C>G) is ultra-rare (popmax 0.0647%, amr) (gnomAD).

What do computational predictors say about VSX1 p.Pro247Arg (c.740C>G)?

AlphaMissense predicts likely pathogenic (score 0.5705) — an in-silico prediction, not a clinical call.

VSX1 p.Pro247Arg

Q: What condition is associated with VSX1 p.Pro247Arg (c.740C>G)?

VSX1 p.Pro247Arg (c.740C>G) is associated with keratoconus 1, craniofacial anomalies and anterior segment dysgenesis syndrome, posterior polymorphous corneal dystrophy (ClinVar).

c.740C>G · rs576300014 · VCV337958

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0647%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

keratoconus 1

Computational evidence

Protein change
AlphaMissense	0.5705	likely pathogenic
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -12.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 5,832 bp · p 0.33 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0647% Admixed American · 33/51,002 alleles

Filtering AF 0.0588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0573%

Overall 0.05% 776/1,550,768 alleles · ultra-rare exomes 710/1,398,496 · genomes 66/152,272 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0647%	1,546
European (non-Finnish)	0.0626%	1,597
Remaining individualsnot grpmax-eligible	0.0283%	3,535
Finnishnot grpmax-eligible	0.00507%	19,731
South Asian	0.00357%	28,015
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,640
African / African-American	0.00137%	73,118

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: VSX1
Protein: p.Pro247Arg
Coding: c.740C>G
MANE Select: NM_014588
dbSNP: rs576300014
Type: single nucleotide variant
Location: chr20:25077753 (GRCh38)
Gene constraint: LOEUF 1.686 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.61
Residue 247: the cvc domain; a UniProt-annotated variant site (in ktcn1; uncertain significance; also in a patient with retinal dysfunction)

Full VSX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

keratoconus 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: craniofacial anomalies and anterior segment dysgenesis syndrome posterior polymorphous corneal dystrophy

Similar variants

VSX1 p.Pro247= Likely benign ★ same residue
VSX1 p.Ala193Val Uncertain significance ★★ ⚠ same condition
VSX1 p.Ala256Ser Uncertain significance ★★ ⚠ same condition
VSX1 p.Ala94Glu Uncertain significance ★★ ⚠ same condition
VSX1 p.Cys55Ter Uncertain significance ★★ same condition
VSX1 p.Gly130Asp Uncertain significance ★★ ⚠ same condition
VSX1 p.Gly347Ter Uncertain significance ★★ same condition
VSX1 p.Pro127Ser Uncertain significance ★★ ⚠ 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/vsx1-p-pro247arg (accessed [today's date]).

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