Is DIP2C p.Arg1539Ter (c.4615C>T) pathogenic?

DIP2C p.Arg1539Ter (c.4615C>T) is classified Conflicting classifications of pathogenicity in DIP2C (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-18). Very rare (popmax 0.000169%, nfe); Associated with DIP2C-associated disorder.

What condition is associated with DIP2C p.Arg1539Ter (c.4615C>T)?

DIP2C p.Arg1539Ter (c.4615C>T) is associated with DIP2C-associated disorder (ClinVar).

How common is DIP2C p.Arg1539Ter (c.4615C>T) in the general population?

DIP2C p.Arg1539Ter (c.4615C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

DIP2C p.Arg1539Ter

c.4615C>T · rs1954570162 · VCV872161

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

DIP2C-associated disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (37 of 37) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.39	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,036 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,888 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.Arg1539Ter
Coding: c.4615C>T
MANE Select: NM_014974
dbSNP: rs1954570162
Type: single nucleotide variant
Location: chr10:277381 (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

DIP2C-associated disorder

Similar variants

DIP2C p.Ser142Ala Uncertain significance ★★ ⚠ same condition
DIP2C c.2268+1G>A Likely pathogenic ★ same condition
DIP2C p.Arg77= Uncertain significance ★ same condition
DIP2C p.Val1440Ile Uncertain significance ★ ⚠ same condition
DIP2C p.Thr501Ser Uncertain significance ⚠ same condition
DIP2C p.Val1105Phe Uncertain significance ⚠ same condition
DIP2C c.1385-4C>T Likely benign same condition
DIP2C p.Leu1137= Likely benign 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-arg1539ter (accessed [today's date]).

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