Is UNC13D p.Arg411fs (c.1229_1230dup) pathogenic?

UNC13D p.Arg411fs (c.12291230dup) is classified Pathogenic/Likely pathogenic in UNC13D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-28). Very rare (popmax 0.00314%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with UNC13D p.Arg411fs (c.1229_1230dup)?

UNC13D p.Arg411fs (c.1229_1230dup) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg411fs (c.1229_1230dup) in the general population?

UNC13D p.Arg411fs (c.1229_1230dup) is very rare (popmax 0.00314%, nfe) (gnomAD).

UNC13D p.Arg411fs

c.1229_1230dup · rs747180228 · VCV1694203

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 32
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.4	phastCons 1
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00314% European (non-Finnish) · 37/1,180,026 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00235% 38/1,613,710 alleles · very rare exomes 36/1,461,482 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,893
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: UNC13D
Protein: p.Arg411fs
Coding: c.1229_1230dup
MANE Select: NM_199242
dbSNP: rs747180228
Type: Duplication
Location: chr17:75836639 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 411: the 'interaction with rab27a' region

Full UNC13D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hemophagocytic lymphohistiocytosis 3

Similar variants

UNC13D p.Arg411Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
UNC13D p.Arg27fs Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.2091+2_2091+3dup Uncertain significance ★★ same condition
UNC13D c.2448-8dup Benign/Likely benign ★★ same condition
UNC13D p.Arg172fs Likely pathogenic ★ same condition
UNC13D p.Arg293fs Pathogenic ★ same condition
UNC13D p.Gln142fs Pathogenic ★ same condition
UNC13D p.His1076fs Likely pathogenic ★ same condition

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/unc13d-p-arg411fs (accessed [today's date]).

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