Is DIP2B p.Arg1350His (c.4049G>A) pathogenic?

DIP2B p.Arg1350His (c.4049G>A) is classified Uncertain significance in DIP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-28). AlphaMissense: ambiguous (0.355); Very rare (popmax 0.000678%, nfe).

How common is DIP2B p.Arg1350His (c.4049G>A) in the general population?

DIP2B p.Arg1350His (c.4049G>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about DIP2B p.Arg1350His (c.4049G>A)?

AlphaMissense predicts ambiguous (score 0.355) — an in-silico prediction, not a clinical call.

DIP2B p.Arg1350His

c.4049G>A · VCV3502054

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Computational evidence

Protein change
AlphaMissense	0.355	ambiguous
REVEL	0.332	indeterminate
SaProt	LLR -7.36	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 240 kb · p 4.2e-21 · regional, not allelic
Overall
CADD	29.5	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 0.000678% European (non-Finnish) · 8/1,180,014 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,014 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: DIP2B
Protein: p.Arg1350His
Coding: c.4049G>A
MANE Select: NM_173602
Type: single nucleotide variant
Location: chr12:50735078 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.83

Full DIP2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIP2B p.Asp501Val Uncertain significance ★★ ⚠ same type
DIP2B p.Cys1071Ser Uncertain significance ★★ ⚠ same type
DIP2B p.His1027Arg Uncertain significance ★★ ⚠ same type
DIP2B p.Ile681Val Uncertain significance ★★ ⚠ same type
DIP2B p.Ile968Thr Uncertain significance ★★ ⚠ same type
DIP2B p.Ile994Leu Uncertain significance ★★ ⚠ same type
DIP2B p.Pro244Ala Uncertain significance ★★ ⚠ same type
DIP2B p.Pro513Ser 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/dip2b-p-arg1350his (accessed [today's date]).

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