Is DIP2A p.Pro640Leu (c.1919C>T) pathogenic?

DIP2A p.Pro640Leu (c.1919C>T) is classified Uncertain significance in DIP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-11). AlphaMissense: likely pathogenic (0.9533); Very rare (popmax 0.00972%, amr).

How common is DIP2A p.Pro640Leu (c.1919C>T) in the general population?

DIP2A p.Pro640Leu (c.1919C>T) is very rare (popmax 0.00972%, amr) (gnomAD).

What do computational predictors say about DIP2A p.Pro640Leu (c.1919C>T)?

AlphaMissense predicts likely pathogenic (score 0.9533) — an in-silico prediction, not a clinical call.

DIP2A p.Pro640Leu

c.1919C>T · rs776089050 · VCV2688931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00972%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9533	likely pathogenic
REVEL	0.576	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 108 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	32.0	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 0.00972% Admixed American · 5/51,432 alleles

Filtering AF 0.0038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00246%

Overall 0.00135% 21/1,550,886 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00972%	10,286
Remaining individualsnot grpmax-eligible	0.00332%	30,124
East Asian	0.00243%	41,132
African / African-American	0.00137%	73,194
South Asian	0.00119%	84,138
European (non-Finnish)	0.000957%	104,455

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.Pro640Leu
Coding: c.1919C>T
MANE Select: NM_015151
dbSNP: rs776089050
Type: single nucleotide variant
Location: chr21:46538600 (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-pro640leu (accessed [today's date]).

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