Is INPP5E p.Ala196Ser (c.586G>T) pathogenic?

INPP5E p.Ala196Ser (c.586G>T) is classified Uncertain significance in INPP5E (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-18). AlphaMissense: likely benign (0.0788); Ultra-rare (popmax 0.0334%, afr); Associated with MORM syndrome.

What condition is associated with INPP5E p.Ala196Ser (c.586G>T)?

INPP5E p.Ala196Ser (c.586G>T) is associated with MORM syndrome, Joubert syndrome 1, Joubert syndrome (ClinVar).

How common is INPP5E p.Ala196Ser (c.586G>T) in the general population?

INPP5E p.Ala196Ser (c.586G>T) is ultra-rare (popmax 0.0334%, afr) (gnomAD).

How is MORM syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about INPP5E p.Ala196Ser (c.586G>T)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

INPP5E p.Ala196Ser

c.586G>T · rs376043087 · VCV1040443

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MORM syndrome

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -5.95	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 -1.1	GERP -1.6
Overall
CADD	5.224	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 0.0334% African / African-American · 25/74,882 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00174% 28/1,610,108 alleles · ultra-rare exomes 14/1,457,918 · genomes 14/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,995
Remaining individualsnot grpmax-eligible	0.00321%	31,149
Admixed American	0.00167%	59,732

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.Ala196Ser
Coding: c.586G>T
MANE Select: NM_019892
dbSNP: rs376043087
Type: single nucleotide variant
Location: chr9:136438834 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

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

Also linked: Joubert syndrome 1 Joubert syndrome

For MORM syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

INPP5E p.Ala196Val Uncertain significance ★★ ⚠ same residue
INPP5E p.Ala196= 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

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-ala196ser (accessed [today's date]).

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