Is INPP5E p.Pro74Ser (c.220C>T) pathogenic?

INPP5E p.Pro74Ser (c.220C>T) is classified Uncertain significance in INPP5E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-29). AlphaMissense: likely benign (0.2638); Very rare (popmax 0.00388%, amr); Associated with MORM syndrome.

What condition is associated with INPP5E p.Pro74Ser (c.220C>T)?

INPP5E p.Pro74Ser (c.220C>T) is associated with MORM syndrome, Joubert syndrome 1 (ClinVar).

How common is INPP5E p.Pro74Ser (c.220C>T) in the general population?

INPP5E p.Pro74Ser (c.220C>T) is very rare (popmax 0.00388%, amr) (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.Pro74Ser (c.220C>T)?

AlphaMissense predicts likely benign (score 0.2638) — an in-silico prediction, not a clinical call.

INPP5E p.Pro74Ser

c.220C>T · VCV3596797

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00388%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MORM syndrome

Computational evidence

Protein change
AlphaMissense	0.2638	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.78	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 7.8	GERP 0.98, phastCons 1
Overall
CADD	22.7	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 0.00388% Admixed American · 2/51,598 alleles

Filtering AF 0.00169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00145%

Overall 0.00357% 55/1,541,252 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0218%	4,596
Remaining individualsnot grpmax-eligible	0.0216%	4,622
Admixed Americangrpmax	0.00388%	25,799
European (non-Finnish)	0.00244%	41,042
East Asian	0.00242%	41,282
African / African-American	0.00136%	73,290

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro74Ser
Coding: c.220C>T
MANE Select: NM_015160 · reported on NM_019892
Type: single nucleotide variant
Location: chr9:136439200 (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

For MORM syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

INPP5E p.Pro74Ala Uncertain significance ★★ ⚠ same residue
INPP5E p.Pro74His Uncertain significance ★ ⚠ same residue
INPP5E p.Pro74= 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

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-pro74ser (accessed [today's date]).

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