Is INPP5A p.Pro8Ser (c.22C>T) pathogenic?

INPP5A p.Pro8Ser (c.22C>T) is classified Uncertain significance in INPP5A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely benign (0.0614); Ultra-rare (popmax 0.0705%, eas).

How common is INPP5A p.Pro8Ser (c.22C>T) in the general population?

INPP5A p.Pro8Ser (c.22C>T) is ultra-rare (popmax 0.0705%, eas) (gnomAD).

What do computational predictors say about INPP5A p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

INPP5A p.Pro8Ser

c.22C>T · rs764513704 · VCV3109803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0705%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -4.14	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 0.85	GERP -0.19, phastCons 0.98
Regional constraint	o/e 0.79	unconstrained · MANE · 244 kb · p 9.2e-07 · regional, not allelic
Overall
CADD	14.94	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 0.0705% East Asian · 22/31,218 alleles

Filtering AF 0.0477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0402%

Overall 0.00218% 27/1,237,106 alleles · ultra-rare exomes 20/1,085,600 · genomes 7/151,506 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0705%	1,419
Remaining individualsnot grpmax-eligible	0.00878%	11,391
European (non-Finnish)	0.000101%	987,030

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: INPP5A
Protein: p.Pro8Ser
Coding: c.22C>T
MANE Select: NM_005539
dbSNP: rs764513704
Type: single nucleotide variant
Location: chr10:132538118 (GRCh38)
Gene constraint: LOEUF 0.356 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.81
Residue 8: the 5-ppase domain

Full INPP5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INPP5A p.Leu237= Benign ★★ same type
INPP5A p.Ser271= Benign ★★ same type
INPP5A c.1158+1G>A Uncertain significance ★ same type
INPP5A c.828+1G>A Uncertain significance ★ same type
INPP5A p.Ala333Thr Uncertain significance ★ ⚠ same type
INPP5A p.Ala403Ser Uncertain significance ★ ⚠ same type
INPP5A p.Ala7Val Uncertain significance ★ ⚠ same type
INPP5A p.Arg206Trp Uncertain significance ★ ⚠ same type

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/inpp5a-p-pro8ser (accessed [today's date]).

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