Is UNC13D p.Pro991= (c.2973G>A) pathogenic?

UNC13D p.Pro991= (c.2973G>A) is classified Conflicting classifications of pathogenicity in UNC13D (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-10). Ultra-rare (popmax 0.012%, afr); Associated with autoinflammatory syndrome.

What condition is associated with UNC13D p.Pro991= (c.2973G>A)?

UNC13D p.Pro991= (c.2973G>A) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Pro991= (c.2973G>A) in the general population?

UNC13D p.Pro991= (c.2973G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

UNC13D p.Pro991=

c.2973G>A · rs564875531 · VCV1096325

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20
Overall
CADD	0.025	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/75,040 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00586% 94/1,604,304 alleles · ultra-rare exomes 76/1,451,934 · genomes 18/152,370 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,338
Admixed American	0.00834%	11,994
Remaining individualsnot grpmax-eligible	0.00802%	12,464
South Asian	0.00659%	15,165
European (non-Finnish)	0.00551%	18,146
East Asian	0.00446%	22,430
Finnishnot grpmax-eligible	0.00359%	27,825

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.Pro991=
Coding: c.2973G>A
MANE Select: NM_199242
dbSNP: rs564875531
Type: single nucleotide variant
Location: chr17:75828965 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 991: the c2 2 domain

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.Pro991Leu 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-pro991 (accessed [today's date]).

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