Is INPP5E p.Pro121Ser (c.361C>T) pathogenic?

INPP5E p.Pro121Ser (c.361C>T) is classified Uncertain significance in INPP5E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.0718); Very rare (popmax 0.00187%, amr); Associated with Joubert syndrome.

What condition is associated with INPP5E p.Pro121Ser (c.361C>T)?

INPP5E p.Pro121Ser (c.361C>T) is associated with Joubert syndrome, Joubert syndrome 1, MORM syndrome (ClinVar).

How common is INPP5E p.Pro121Ser (c.361C>T) in the general population?

INPP5E p.Pro121Ser (c.361C>T) is very rare (popmax 0.00187%, amr) (gnomAD).

What do computational predictors say about INPP5E p.Pro121Ser (c.361C>T)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

INPP5E p.Pro121Ser

c.361C>T · rs1193322281 · VCV1943771

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -0.18, phastCons 0.001
Overall
CADD	7.506	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00187% Admixed American · 1/53,348 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000191% 3/1,568,154 alleles · very rare exomes 3/1,415,886 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00187%	53,348
European (non-Finnish)	0.000173%	578,697

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.Pro121Ser
Coding: c.361C>T
MANE Select: NM_019892
dbSNP: rs1193322281
Type: single nucleotide variant
Location: chr9:136439059 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

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

Also linked: Joubert syndrome 1 MORM syndrome

Similar variants

INPP5E p.Pro121= Likely benign ★★ same residue
PMPCA p.Ala121Ser 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

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-pro121ser (accessed [today's date]).

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