Is UNC13D p.Pro38= (c.114G>A) pathogenic?

UNC13D p.Pro38= (c.114G>A) is classified Conflicting classifications of pathogenicity in UNC13D (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0318%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with UNC13D p.Pro38= (c.114G>A)?

UNC13D p.Pro38= (c.114G>A) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Pro38= (c.114G>A) in the general population?

UNC13D p.Pro38= (c.114G>A) is ultra-rare (popmax 0.0318%, nfe) (gnomAD).

UNC13D p.Pro38=

c.114G>A · rs755103812 · VCV721239

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, nfe)

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 -0.56
Overall
CADD	6.281	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0318% European (non-Finnish) · 375/1,179,950 alleles

Filtering AF 0.0291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.028%

Overall 0.0289% 465/1,611,570 alleles · ultra-rare exomes 435/1,459,358 · genomes 30/152,212 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.199%	502
European (non-Finnish)grpmax	0.0318%	3,147
Remaining individualsnot grpmax-eligible	0.024%	4,164
Middle Eastern	0.0165%	6,076
Finnishnot grpmax-eligible	0.0162%	6,164
Admixed American	0.005%	20,002
African / African-American	0.00133%	74,922
South Asian	0.0011%	91,088

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro38=
Coding: c.114G>A
MANE Select: NM_199242
dbSNP: rs755103812
Type: single nucleotide variant
Location: chr17:75844224 (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

Similar variants

UNC13D p.Pro38Arg Benign/Likely benign ★★ same residue
UNC13D p.Pro38Leu 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

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-pro38 (accessed [today's date]).

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