Is PAX2 p.Pro320His (c.959C>A) pathogenic?

PAX2 p.Pro320His (c.959C>A) is classified Uncertain significance in PAX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). AlphaMissense: likely pathogenic (0.9835); Very rare (popmax 0.0022%, sas); Associated with focal segmental glomerulosclerosis 7.

What condition is associated with PAX2 p.Pro320His (c.959C>A)?

PAX2 p.Pro320His (c.959C>A) is associated with focal segmental glomerulosclerosis 7, renal coloboma syndrome (ClinVar).

How common is PAX2 p.Pro320His (c.959C>A) in the general population?

PAX2 p.Pro320His (c.959C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PAX2 p.Pro320His (c.959C>A)?

AlphaMissense predicts likely pathogenic (score 0.9835) — an in-silico prediction, not a clinical call.

PAX2 p.Pro320His

c.959C>A · VCV4793656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

focal segmental glomerulosclerosis 7

Computational evidence

Protein change
AlphaMissense	0.9835	likely pathogenic
REVEL	0.447	indeterminate
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.4 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P343H vs ClinVar P320H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,022 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000931% 15/1,611,330 alleles · very rare exomes 15/1,459,078 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,511
Remaining individualsnot grpmax-eligible	0.0016%	62,414
European (non-Finnish)	0.00102%	98,123

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: PAX2
Protein: p.Pro320His
Coding: c.959C>A
MANE Select: NM_000278
Type: single nucleotide variant
Location: chr10:100824687 (GRCh38)
Gene constraint: LOEUF 0.451 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.52

Full PAX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

focal segmental glomerulosclerosis 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal coloboma syndrome

Similar variants

PAX2 p.Pro320Arg Uncertain significance ★ ⚠ same residue
PAX2 p.Pro320Leu Uncertain significance ★ ⚠ same residue
PAX2 c.212+1G>T Pathogenic/Likely pathogenic ★★ same condition
PAX2 c.213-8C>A Likely pathogenic ★★ same condition
PAX2 c.792+2T>C Pathogenic ★★ same condition
PAX2 p.Arg104Ter Pathogenic ★★ same condition
PAX2 p.Arg115Ter Pathogenic ★★ same condition
PAX2 p.Arg140Trp 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/pax2-p-pro320his (accessed [today's date]).

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