Is DIP2C p.Ile366Phe (c.1096A>T) pathogenic?

DIP2C p.Ile366Phe (c.1096A>T) is classified Uncertain significance in DIP2C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: ambiguous (0.3774); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DIP2C p.Ile366Phe (c.1096A>T)?

DIP2C p.Ile366Phe (c.1096A>T) is associated with Inborn genetic diseases (ClinVar).

How common is DIP2C p.Ile366Phe (c.1096A>T) in the general population?

DIP2C p.Ile366Phe (c.1096A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DIP2C p.Ile366Phe (c.1096A>T)?

AlphaMissense predicts ambiguous (score 0.3774) — an in-silico prediction, not a clinical call.

DIP2C p.Ile366Phe

c.1096A>T · rs921460668 · VCV2338687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3774	ambiguous
REVEL	0.161	moderately benign-leaning
SaProt	LLR -9.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 290 kb · p 0.0041 · regional, not allelic
Overall
CADD	23.4	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 0.000254% European (non-Finnish) · 3/1,180,044 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,098 alleles · very rare

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: DIP2C
Protein: p.Ile366Phe
Coding: c.1096A>T
MANE Select: NM_014974
dbSNP: rs921460668
Type: single nucleotide variant
Location: chr10:408979 (GRCh38)
Gene constraint: LOEUF 0.235 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.64

Full DIP2C 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

DIP2C p.Ile366Val Uncertain significance ★ ⚠ same residue
DIP2C p.Ala1066Val Uncertain significance ★★ ⚠ same condition
DIP2C p.Ala1101Val Uncertain significance ★★ ⚠ same condition
DIP2C p.Ala1155Thr Uncertain significance ★★ ⚠ same condition
DIP2C p.Ala1466Thr Uncertain significance ★★ ⚠ same condition
DIP2C p.Ala193Val Uncertain significance ★★ ⚠ same condition
DIP2C p.Ala422Thr Uncertain significance ★★ ⚠ same condition
DIP2C p.Ala71Thr 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/dip2c-p-ile366phe (accessed [today's date]).

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