Is INPP5E p.Ser249Phe (c.746C>T) pathogenic?

INPP5E p.Ser249Phe (c.746C>T) is classified Conflicting classifications of pathogenicity in INPP5E (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-03-03). AlphaMissense: likely benign (0.2152); Ultra-rare (popmax 0.0281%, amr); Associated with INPP5E-related disorder.

What condition is associated with INPP5E p.Ser249Phe (c.746C>T)?

INPP5E p.Ser249Phe (c.746C>T) is associated with INPP5E-related disorder, Joubert syndrome 1, MORM syndrome (ClinVar).

How common is INPP5E p.Ser249Phe (c.746C>T) in the general population?

INPP5E p.Ser249Phe (c.746C>T) is ultra-rare (popmax 0.0281%, amr) (gnomAD).

What do computational predictors say about INPP5E p.Ser249Phe (c.746C>T)?

AlphaMissense predicts likely benign (score 0.2152) — an in-silico prediction, not a clinical call.

INPP5E p.Ser249Phe

c.746C>T · rs550485638 · VCV1065823

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.2152 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

INPP5E-related disorder

Computational evidence

Protein change
AlphaMissense	0.2152	likely benign
REVEL	0.574	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.1, phastCons 1
Overall
CADD	26.1	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 0.0281% Admixed American · 16/56,870 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.00414% 66/1,594,240 alleles · ultra-rare exomes 58/1,441,890 · genomes 8/152,350 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0281%	3,554
Remaining individualsnot grpmax-eligible	0.00973%	10,278
European (non-Finnish)	0.00376%	26,611

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.Ser249Phe
Coding: c.746C>T
MANE Select: NM_019892
dbSNP: rs550485638
Type: single nucleotide variant
Location: chr9:136438674 (GRCh38)
Structure: AlphaFold pLDDT 88.46

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

Disease context

INPP5E-related disorder

Also linked: Joubert syndrome 1 MORM syndrome Joubert syndrome inherited retinal dystrophy

Similar variants

INPP5E p.Ser249= Likely benign ★★ same residue
INPP5E p.Ser249Cys Uncertain significance ★ ⚠ same residue
INPP5E c.937-2A>G Pathogenic/Likely pathogenic ★★ same condition
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-ser249phe (accessed [today's date]).

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