Is DZIP3 p.Arg409Gln (c.1226G>A) pathogenic?

DZIP3 p.Arg409Gln (c.1226G>A) is classified Uncertain significance in DZIP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-31). AlphaMissense: ambiguous (0.4397); Ultra-rare (popmax 0.0164%, mid).

How common is DZIP3 p.Arg409Gln (c.1226G>A) in the general population?

DZIP3 p.Arg409Gln (c.1226G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DZIP3 p.Arg409Gln (c.1226G>A)?

AlphaMissense predicts ambiguous (score 0.4397) — an in-silico prediction, not a clinical call.

DZIP3 p.Arg409Gln

c.1226G>A · rs377325943 · VCV3086712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4397 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4397	ambiguous
REVEL	0.132	moderately benign-leaning
SaProt	LLR -10.24	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 83 kb · p 0.28 · regional, not allelic
Overall
CADD	24.9	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00198% 32/1,613,400 alleles · ultra-rare exomes 29/1,461,478 · genomes 3/151,922 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
East Asian	0.00446%	22,428
Admixed American	0.00334%	29,975
Remaining individualsnot grpmax-eligible	0.0032%	31,237
South Asian	0.0022%	45,518
European (non-Finnish)	0.00195%	51,297

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: DZIP3
Protein: p.Arg409Gln
Coding: c.1226G>A
MANE Select: NM_014648
dbSNP: rs377325943
Type: single nucleotide variant
Location: chr3:108644248 (GRCh38)
Gene constraint: LOEUF 0.781 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.63

Full DZIP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DZIP3 c.456+10A>G Benign ★★ same type
DZIP3 p.Asp6Gly Benign ★★ same type
DZIP3 p.Ala1018Ser Uncertain significance ★ ⚠ same type
DZIP3 p.Ala114Val Uncertain significance ★ ⚠ same type
DZIP3 p.Ala14Thr Uncertain significance ★ ⚠ same type
DZIP3 p.Ala714Thr Uncertain significance ★ ⚠ same type
DZIP3 p.Ala793Thr Uncertain significance ★ ⚠ same type
DZIP3 p.Ala854Thr 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/dzip3-p-arg409gln (accessed [today's date]).

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