Is UNC13D p.Glu575= (c.1725G>A) pathogenic?

UNC13D p.Glu575= (c.1725G>A) is classified Likely benign in UNC13D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). Ultra-rare (popmax 0.0934%, afr); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Glu575= (c.1725G>A)?

UNC13D p.Glu575= (c.1725G>A) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Glu575= (c.1725G>A) in the general population?

UNC13D p.Glu575= (c.1725G>A) is ultra-rare (popmax 0.0934%, afr) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

UNC13D p.Glu575=

c.1725G>A · rs150521730 · VCV1577380

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0934%, afr)

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 0.018	phastCons 0.015
Overall
CADD	0.749	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0934% African / African-American · 70/74,954 alleles

Filtering AF 0.0757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0693%

Overall 0.00446% 72/1,613,188 alleles · ultra-rare exomes 37/1,460,928 · genomes 35/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0934%	1,071
Finnishnot grpmax-eligible	0.00158%	63,128
South Asian	0.0011%	91,094

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.Glu575=
Coding: c.1725G>A
MANE Select: NM_199242
dbSNP: rs150521730
Type: single nucleotide variant
Location: chr17:75835649 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 575: the mhd1 domain

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 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
UNC13D c.2447+2T>C 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-glu575 (accessed [today's date]).

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