Is INPP5E p.Pro154Ser (c.460C>T) pathogenic?

INPP5E p.Pro154Ser (c.460C>T) is classified Uncertain significance in INPP5E (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0658%, afr); Associated with Inborn genetic diseases.

What condition is associated with INPP5E p.Pro154Ser (c.460C>T)?

INPP5E p.Pro154Ser (c.460C>T) is associated with Inborn genetic diseases, Joubert syndrome 1, MORM syndrome (ClinVar).

How common is INPP5E p.Pro154Ser (c.460C>T) in the general population?

INPP5E p.Pro154Ser (c.460C>T) is ultra-rare (popmax 0.0658%, afr) (gnomAD).

What do computational predictors say about INPP5E p.Pro154Ser (c.460C>T)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

INPP5E p.Pro154Ser

c.460C>T · rs565209005 · VCV844000

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.11	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 4.3	GERP -0.19, phastCons 1
Overall
CADD	13.86	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 0.0658% African / African-American · 49/74,420 alleles

Filtering AF 0.0511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0459%

Overall 0.0202% 318/1,572,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0658%	1,519
Middle Eastern	0.0336%	2,978
Remaining individualsnot grpmax-eligible	0.023%	4,351
European (non-Finnish)	0.0206%	4,852
Admixed American	0.0132%	7,594
Finnishnot grpmax-eligible	0.0101%	9,944
South Asian	0.00116%	86,444

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.Pro154Ser
Coding: c.460C>T
MANE Select: NM_015160 · reported on NM_019892
dbSNP: rs565209005
Type: single nucleotide variant
Location: chr9:136438960 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 1 MORM syndrome Joubert syndrome

Similar variants

INPP5E p.Pro154= Likely benign ★ 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-pro154ser (accessed [today's date]).

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