Is VSX2 p.Pro231Ser (c.691C>T) pathogenic?

VSX2 p.Pro231Ser (c.691C>T) is classified Uncertain significance in VSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.9947); Very rare (popmax 0.00133%, afr).

How common is VSX2 p.Pro231Ser (c.691C>T) in the general population?

VSX2 p.Pro231Ser (c.691C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about VSX2 p.Pro231Ser (c.691C>T)?

AlphaMissense predicts likely pathogenic (score 0.9947) — an in-silico prediction, not a clinical call.

VSX2 p.Pro231Ser

c.691C>T · VCV4281953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9947	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -11.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.43 · regional, not allelic
Overall
CADD	31.0	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 0.00133% African / African-American · 1/74,930 alleles

Overall 6.2e-05% 1/1,613,688 alleles · very rare exomes 0/1,461,476 · genomes 1/152,212 · joint denominator

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.Pro231Ser
Coding: c.691C>T
MANE Select: NM_182894
Type: single nucleotide variant
Location: chr14:74259713 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.65
Residue 231: the cvc domain

Full VSX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VSX2 c.371-1G>A Pathogenic ★★ same type
VSX2 p.Arg200Gln Pathogenic ★★ same type
VSX2 p.Arg200Pro Pathogenic/Likely pathogenic ★★ same type
VSX2 p.Arg200Ter Pathogenic ★★ same type
VSX2 p.Arg227Trp Pathogenic/Likely pathogenic ★★ same type
VSX2 p.Cys29Ter Pathogenic/Likely pathogenic ★★ same type
VSX2 p.Gln197Ter Pathogenic/Likely pathogenic ★★ same type
VSX2 p.Trp195Ter Pathogenic/Likely pathogenic ★★ same type

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-pro231ser (accessed [today's date]).

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