Is UNC13D p.Arg52Gln (c.155G>A) pathogenic?

UNC13D p.Arg52Gln (c.155G>A) is classified Uncertain significance in UNC13D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-04). AlphaMissense: likely benign (0.0777); Ultra-rare (popmax 0.0501%, mid); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Arg52Gln (c.155G>A)?

UNC13D p.Arg52Gln (c.155G>A) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg52Gln (c.155G>A) in the general population?

UNC13D p.Arg52Gln (c.155G>A) is ultra-rare (popmax 0.0501%, mid) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

What do computational predictors say about UNC13D p.Arg52Gln (c.155G>A)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

UNC13D p.Arg52Gln

c.155G>A · rs750613531 · VCV859773

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hemophagocytic lymphohistiocytosis 3

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ1.00	acceptor gain · deltas
Pangolin	Δ0.86	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.7	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0501% Middle Eastern · 3/5,990 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.000996% 16/1,606,152 alleles · ultra-rare exomes 14/1,454,222 · genomes 2/151,930 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0501%	1,997
East Asian	0.0112%	8,968
Remaining individualsnot grpmax-eligible	0.0032%	31,206
Finnishnot grpmax-eligible	0.00176%	56,674
Admixed American	0.00167%	59,970
African / African-American	0.00134%	74,836
European (non-Finnish)	0.000254%	393,284

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.Arg52Gln
Coding: c.155G>A
MANE Select: NM_199242
dbSNP: rs750613531
Type: single nucleotide variant
Location: chr17:75843265 (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.Arg52Trp Uncertain significance ★★ ⚠ same residue
UNC13D p.Arg52= Conflicting classifications of pathogenicity ★ 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-arg52gln (accessed [today's date]).

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