Is INPP5A p.Arg35Pro (c.104G>C) pathogenic?

INPP5A p.Arg35Pro (c.104G>C) is classified Uncertain significance in INPP5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.9075); Very rare (popmax 0.00161%, nfe).

How common is INPP5A p.Arg35Pro (c.104G>C) in the general population?

INPP5A p.Arg35Pro (c.104G>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about INPP5A p.Arg35Pro (c.104G>C)?

AlphaMissense predicts likely pathogenic (score 0.9075) — an in-silico prediction, not a clinical call.

INPP5A p.Arg35Pro

c.104G>C · VCV4275577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9075	likely pathogenic
REVEL	0.154	moderately benign-leaning
SaProt	LLR -13.49	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 244 kb · p 9.2e-07 · regional, not allelic
Overall
CADD	24.4	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 0.00161% European (non-Finnish) · 19/1,179,964 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,611,744 alleles · very rare exomes 17/1,459,506 · genomes 2/152,238 · 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: INPP5A
Protein: p.Arg35Pro
Coding: c.104G>C
MANE Select: NM_005539
Type: single nucleotide variant
Location: chr10:132607943 (GRCh38)
Gene constraint: LOEUF 0.356 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.81
Residue 35: the 5-ppase domain

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

Similar variants

INPP5A p.Arg35Gln Uncertain significance ★ ⚠ same residue
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

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-arg35pro (accessed [today's date]).

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