Is DIP2A p.Val1455Ile (c.4363G>A) pathogenic?

DIP2A p.Val1455Ile (c.4363G>A) is classified Uncertain significance in DIP2A (ClinVar, Single submitter, 2 submitters; last evaluated 2022-10-06). AlphaMissense: likely benign (0.1283); Ultra-rare (popmax 0.0398%, nfe).

How common is DIP2A p.Val1455Ile (c.4363G>A) in the general population?

DIP2A p.Val1455Ile (c.4363G>A) is ultra-rare (popmax 0.0398%, nfe) (gnomAD).

What do computational predictors say about DIP2A p.Val1455Ile (c.4363G>A)?

AlphaMissense predicts likely benign (score 0.1283) — an in-silico prediction, not a clinical call.

DIP2A p.Val1455Ile

c.4363G>A · rs200244740 · VCV2376111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1283 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0398%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1283	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 108 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0398% European (non-Finnish) · 470/1,179,990 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.0412% 665/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.261%	383
European (non-Finnish)grpmax	0.0398%	2,511
Remaining individualsnot grpmax-eligible	0.0352%	2,840
African / African-American	0.00534%	18,733
Admixed American	0.00333%	29,998

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DIP2A
Protein: p.Val1455Ile
Coding: c.4363G>A
MANE Select: NM_015151
dbSNP: rs200244740
Type: single nucleotide variant
Location: chr21:46566583 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93

Full DIP2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIP2A p.Ala676Thr Uncertain significance ★★ ⚠ same type
DIP2A p.Glu832Lys Uncertain significance ★★ ⚠ same type
DIP2A p.Pro333= Benign ★★ same type
DIP2A p.Pro798Leu Benign/Likely benign ★★ ⚠ same type
DIP2A p.Thr848= Benign/Likely benign ★★ same type
DIP2A p.Val1531= Benign ★★ same type
DIP2A c.1429+2T>G Likely pathogenic ★ same type
DIP2A c.2395-2A>G 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/dip2a-p-val1455ile (accessed [today's date]).

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