Is DPPA2 p.Val221Ile (c.661G>A) pathogenic?

DPPA2 p.Val221Ile (c.661G>A) is classified Uncertain significance in DPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely benign (0.0901); Ultra-rare (popmax 0.0137%, nfe).

How common is DPPA2 p.Val221Ile (c.661G>A) in the general population?

DPPA2 p.Val221Ile (c.661G>A) is ultra-rare (popmax 0.0137%, nfe) (gnomAD).

What do computational predictors say about DPPA2 p.Val221Ile (c.661G>A)?

AlphaMissense predicts likely benign (score 0.0901) — an in-silico prediction, not a clinical call.

DPPA2 p.Val221Ile

c.661G>A · rs199811743 · VCV2397623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0901 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0901	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -7.06	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 -2.9	GERP -4.2
Regional constraint	o/e 0.99	unconstrained · MANE · 14 kb · p 0.83 · regional, not allelic
Overall
CADD	6.388	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 0.0137% European (non-Finnish) · 160/1,165,902 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.011% 174/1,581,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0137%	7,287
Remaining individualsnot grpmax-eligible	0.00655%	15,256
African / African-American	0.00546%	18,325
South Asian	0.00463%	21,594
East Asian	0.00228%	43,908
Admixed American	0.00191%	52,228

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: DPPA2
Protein: p.Val221Ile
Coding: c.661G>A
MANE Select: NM_138815
dbSNP: rs199811743
Type: single nucleotide variant
Location: chr3:109304668 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.63

Full DPPA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPPA2 p.Arg131Gln Benign ★★ same type
DPPA2 p.Leu278Ser Likely pathogenic ★ same type
DPPA2 p.Arg131Trp Uncertain significance ★ ⚠ same type
DPPA2 p.Arg142Thr Uncertain significance ★ ⚠ same type
DPPA2 p.Arg145Gln Uncertain significance ★ ⚠ same type
DPPA2 p.Arg150Cys Uncertain significance ★ ⚠ same type
DPPA2 p.Arg150His Uncertain significance ★ ⚠ same type
DPPA2 p.Arg240His 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/dppa2-p-val221ile (accessed [today's date]).

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