Is INPP5B p.Pro74Ser (c.220C>T) pathogenic?

INPP5B p.Pro74Ser (c.220C>T) is classified Uncertain significance in INPP5B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-11). AlphaMissense: ambiguous (0.3769); Very rare (popmax 0.000424%, nfe); Associated with INPP5B-related disorder.

What condition is associated with INPP5B p.Pro74Ser (c.220C>T)?

INPP5B p.Pro74Ser (c.220C>T) is associated with INPP5B-related disorder (ClinVar).

How common is INPP5B p.Pro74Ser (c.220C>T) in the general population?

INPP5B p.Pro74Ser (c.220C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about INPP5B p.Pro74Ser (c.220C>T)?

AlphaMissense predicts ambiguous (score 0.3769) — an in-silico prediction, not a clinical call.

INPP5B p.Pro74Ser

c.220C>T · VCV3349660

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

INPP5B-related disorder

Computational evidence

Protein change
AlphaMissense	0.3769	ambiguous
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 57 kb · p 0.4 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,968 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,076 alleles · very rare exomes 5/1,461,814 · genomes 0/152,262 · joint denominator

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: INPP5B
Protein: p.Pro74Ser
Coding: c.220C>T
MANE Select: NM_005540
Type: single nucleotide variant
Location: chr1:37943826 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.88 · 5 PDB
Residue 74: the ph domain

Full INPP5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

INPP5B-related disorder

Similar variants

INPP5B c.532+213G>T Benign same condition
INPP5B c.532+215C>T Benign same condition
INPP5B p.Ala366= Likely benign same condition
INPP5B p.Glu321= Likely benign same condition
INPP5B p.Ile291= Benign same condition
INPP5B p.Ile558= Likely benign same condition
INPP5B p.Ile92Asn Benign same condition
INPP5B p.Leu252= Likely benign 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/inpp5b-p-pro74ser (accessed [today's date]).

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