Is PAX6 p.Pro20Ser (c.58C>T) pathogenic?

PAX6 p.Pro20Ser (c.58C>T) is classified Uncertain significance in PAX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). AlphaMissense: likely pathogenic (0.9997); Very rare (popmax 0.00223%, eas); Associated with aniridia 1.

What condition is associated with PAX6 p.Pro20Ser (c.58C>T)?

PAX6 p.Pro20Ser (c.58C>T) is associated with aniridia 1, Peters anomaly (ClinVar).

How common is PAX6 p.Pro20Ser (c.58C>T) in the general population?

PAX6 p.Pro20Ser (c.58C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PAX6 p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

PAX6 p.Pro20Ser

c.58C>T · rs2496303548 · VCV2933344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aniridia 1

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic
REVEL	0.927	moderately pathogenic-leaning
SaProt	LLR -16.16	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 4,536 bp · p 4e-05 · regional, not allelic
Overall
CADD	28.1	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 0.00223% East Asian · 1/44,864 alleles

Overall 6.2e-05% 1/1,614,080 alleles · very rare exomes 1/1,461,834 · genomes 0/152,246 · 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: PAX6
Protein: p.Pro20Ser
Coding: c.58C>T
MANE Select: NM_001368894
dbSNP: rs2496303548
Type: single nucleotide variant
Location: chr11:31802787 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.35 · 2 PDB
Residue 20: a DNA-binding region; the 'pai subdomain' region; an α-helix

Full PAX6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Peters anomaly

Similar variants

PAX6 p.Pro20= Likely benign ★ same residue
PAX6 c.1074+1G>C Pathogenic ★★ same condition
PAX6 c.1075-2A>G Pathogenic ★★ same condition
PAX6 c.1225+5G>A Pathogenic/Likely pathogenic ★★ same condition
PAX6 c.141+1G>A Pathogenic ★★ same condition
PAX6 c.399+1G>A Pathogenic ★★ same condition
PAX6 c.399+1G>C Pathogenic ★★ same condition
PAX6 c.958+1G>A 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/pax6-p-pro20ser (accessed [today's date]).

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