Is UNC13D p.Ala730= (c.2190C>T) pathogenic?

UNC13D p.Ala730= (c.2190C>T) is classified Likely benign in UNC13D (ClinVar, Single submitter, 2 submitters; last evaluated 2023-07-30). Very rare (popmax 0.00344%, sas); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Ala730= (c.2190C>T)?

UNC13D p.Ala730= (c.2190C>T) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Ala730= (c.2190C>T) in the general population?

UNC13D p.Ala730= (c.2190C>T) is very rare (popmax 0.00344%, sas) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

UNC13D p.Ala730=

c.2190C>T · rs756842152 · VCV2175022

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00344%, sas)

Conditions

familial hemophagocytic lymphohistiocytosis 3

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 -3.1
Overall
CADD	1.769	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00344% South Asian · 3/87,196 alleles

Filtering AF 0.000914% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000453%

Overall 0.00102% 16/1,569,342 alleles · very rare exomes 15/1,417,120 · genomes 1/152,222 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00344%	29,065
Remaining individualsnot grpmax-eligible	0.00327%	30,557
African / African-American	0.00135%	74,178
European (non-Finnish)	0.00086%	116,295

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.Ala730=
Coding: c.2190C>T
MANE Select: NM_199242
dbSNP: rs756842152
Type: single nucleotide variant
Location: chr17:75834433 (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

familial hemophagocytic lymphohistiocytosis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

UNC13D p.Ala730fs Pathogenic ★ 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-ala730 (accessed [today's date]).

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