Is DIP2A p.Arg537Trp (c.1609C>T) pathogenic?

DIP2A p.Arg537Trp (c.1609C>T) is classified Uncertain significance in DIP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0911); Rare (popmax 0.146%, nfe).

How common is DIP2A p.Arg537Trp (c.1609C>T) in the general population?

DIP2A p.Arg537Trp (c.1609C>T) is rare (popmax 0.146%, nfe) (gnomAD).

What do computational predictors say about DIP2A p.Arg537Trp (c.1609C>T)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

DIP2A p.Arg537Trp

c.1609C>T · rs201190474 · VCV2360162

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.146%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -7.65	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 2.7	GERP 1.8, phastCons 0.12
Regional constraint	o/e 0.85	unconstrained · MANE · 108 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	24.2	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 0.146% European (non-Finnish) · 1,728/1,179,838 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.138%

Overall 0.115% 1,855/1,611,708 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.146%	683
Remaining individualsnot grpmax-eligible	0.0736%	1,358
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
African / African-American	0.04%	2,499
Admixed American	0.0383%	2,608
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.00484%	20,649
East Asian	0.00446%	22,427
South Asian	0.0022%	45,528

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.Arg537Trp
Coding: c.1609C>T
MANE Select: NM_015151
dbSNP: rs201190474
Type: single nucleotide variant
Location: chr21:46534654 (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.Arg537Gln Uncertain significance ★ ⚠ same residue
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

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-arg537trp (accessed [today's date]).

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