Is INPP5E p.Ser136Phe (c.407C>T) pathogenic?

INPP5E p.Ser136Phe (c.407C>T) is classified Uncertain significance in INPP5E (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: likely benign (0.3245); Very rare (popmax 0.00179%, amr); Associated with Inborn genetic diseases.

What condition is associated with INPP5E p.Ser136Phe (c.407C>T)?

INPP5E p.Ser136Phe (c.407C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INPP5E p.Ser136Phe (c.407C>T) in the general population?

INPP5E p.Ser136Phe (c.407C>T) is very rare (popmax 0.00179%, amr) (gnomAD).

What do computational predictors say about INPP5E p.Ser136Phe (c.407C>T)?

AlphaMissense predicts likely benign (score 0.3245) — an in-silico prediction, not a clinical call.

INPP5E p.Ser136Phe

c.407C>T · rs1455030345 · VCV2475191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3245 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3245	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -10.29	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.98, phastCons 1
Overall
CADD	27.6	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 0.00179% Admixed American · 1/55,768 alleles

Overall 6.3e-05% 1/1,587,368 alleles · very rare exomes 1/1,435,032 · genomes 0/152,336 · 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: INPP5E
Protein: p.Ser136Phe
Coding: c.407C>T
MANE Select: NM_019892
dbSNP: rs1455030345
Type: single nucleotide variant
Location: chr9:136439013 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INPP5E p.Ser136= Likely benign ★ same residue
INPP5E p.Ala105Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala123Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala291Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala36Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala503Ser Uncertain significance ★★ ⚠ same condition
INPP5E p.Arg251Pro Uncertain significance ★★ ⚠ same condition
INPP5E p.Arg297Gln Uncertain significance ★★ ⚠ 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-ser136phe (accessed [today's date]).

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