Is UNC13D p.Arg83Ter (c.247C>T) pathogenic?

UNC13D p.Arg83Ter (c.247C>T) is classified Pathogenic/Likely pathogenic in UNC13D (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-15). Very rare (popmax 0.00446%, eas); Associated with autoinflammatory syndrome.

What condition is associated with UNC13D p.Arg83Ter (c.247C>T)?

UNC13D p.Arg83Ter (c.247C>T) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 3, hereditary hemophagocytic lymphohistiocytosis (ClinVar).

How common is UNC13D p.Arg83Ter (c.247C>T) in the general population?

UNC13D p.Arg83Ter (c.247C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

UNC13D p.Arg83Ter

c.247C>T · rs1274685768 · VCV631788

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 32
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.54
Overall
CADD	36.0	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 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000806% 13/1,612,124 alleles · very rare exomes 13/1,459,916 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
South Asian	0.0011%	91,076
European (non-Finnish)	0.000847%	117,995

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.Arg83Ter
Coding: c.247C>T
MANE Select: NM_199242
dbSNP: rs1274685768
Type: single nucleotide variant
Location: chr17:75843173 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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 hereditary hemophagocytic lymphohistiocytosis

Similar variants

UNC13D p.Arg83Gln Uncertain significance ★★ ⚠ same residue
UNC13D c.1055+1G>A Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.118-307G>A Pathogenic ★★ same condition
UNC13D c.118-308C>T Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.1389+1G>A Pathogenic ★★ same condition
UNC13D c.1596+1G>C Pathogenic ★★ same condition
UNC13D c.1727+1G>A Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.1848+1G>A Pathogenic/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-arg83ter (accessed [today's date]).

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