Is DIP2A p.Ala194Pro (c.580G>C) pathogenic?

DIP2A p.Ala194Pro (c.580G>C) is classified Uncertain significance in DIP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0708); Ultra-rare (popmax 0.0253%, afr).

How common is DIP2A p.Ala194Pro (c.580G>C) in the general population?

DIP2A p.Ala194Pro (c.580G>C) is ultra-rare (popmax 0.0253%, afr) (gnomAD).

What do computational predictors say about DIP2A p.Ala194Pro (c.580G>C)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

DIP2A p.Ala194Pro

c.580G>C · VCV4834982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.74	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 0.81	GERP 0.99
Regional constraint	o/e 0.85	unconstrained · MANE · 108 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	18.39	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 0.0253% African / African-American · 19/75,016 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.0018% 29/1,613,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0253%	3,948
Remaining individualsnot grpmax-eligible	0.0064%	15,621
South Asian	0.0022%	45,539
European (non-Finnish)	0.000339%	294,964

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.Ala194Pro
Coding: c.580G>C
MANE Select: NM_015151
Type: single nucleotide variant
Location: chr21:46498758 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93
Residue 194: the 'disordered' region

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

Similar variants

DIP2A p.Ala194Asp 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-ala194pro (accessed [today's date]).

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