Is INPP5E p.Pro324= (c.972A>G) pathogenic?

INPP5E p.Pro324= (c.972A>G) is classified Benign in INPP5E (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 24.5%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Joubert syndrome 1.

What condition is associated with INPP5E p.Pro324= (c.972A>G)?

INPP5E p.Pro324= (c.972A>G) is associated with Joubert syndrome 1, MORM syndrome, Joubert syndrome (ClinVar).

INPP5E p.Pro324=

Q: How common is INPP5E p.Pro324= (c.972A>G) in the general population?

INPP5E p.Pro324= (c.972A>G) is common (popmax 24.5%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.972A>G · rs10870199 · VCV129277

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 24.5%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

Joubert syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.2	GERP -2
Overall
CADD	3.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 24.5% Admixed American · 14,635/59,684 alleles

Filtering AF 24.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.1%

Overall 13.7% 221,130/1,609,748 alleles · common exomes 204,771/1,457,504 · genomes 16,359/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	24.5%	4
South Asian	16.1%	6
East Asian	14.7%	7
European (non-Finnish)	14.1%	7
Remaining individualsnot grpmax-eligible	13.4%	7
Middle Eastern	11.8%	9
Ashkenazi Jewishnot grpmax-eligible	11.3%	9
Amishnot grpmax-eligible	7.69%	13
Finnishnot grpmax-eligible	7.3%	14
African / African-American	2.55%	39

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: INPP5E
Protein: p.Pro324=
Coding: c.972A>G
MANE Select: NM_019892
dbSNP: rs10870199
Type: single nucleotide variant
Location: chr9:136434099 (GRCh38)
Structure: AlphaFold pLDDT 88.46

Full INPP5E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: MORM syndrome Joubert syndrome

Similar variants

INPP5E p.Pro324Leu Uncertain significance ★ same residue
INPP5E p.Arg378Cys Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg435Gln Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg435Trp Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg557His Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg563His Likely pathogenic ★★ ⚠ same condition
INPP5E p.Arg585Cys Pathogenic/Likely pathogenic ★★ same condition
INPP5E p.Arg621Gln Pathogenic/Likely 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/inpp5e-p-pro324 (accessed [today's date]).

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