Is UNC13D p.Arg52Trp (c.154C>T) pathogenic?

UNC13D p.Arg52Trp (c.154C>T) is classified Uncertain significance in UNC13D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-26). AlphaMissense: likely benign (0.1378); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with UNC13D p.Arg52Trp (c.154C>T)?

UNC13D p.Arg52Trp (c.154C>T) is associated with Inborn genetic diseases, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg52Trp (c.154C>T) in the general population?

UNC13D p.Arg52Trp (c.154C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about UNC13D p.Arg52Trp (c.154C>T)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

UNC13D p.Arg52Trp

c.154C>T · rs930596937 · VCV1956037

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -10.71	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.4	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,856 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00143% 23/1,606,010 alleles · very rare exomes 18/1,454,100 · genomes 5/151,910 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,428
South Asian	0.0022%	45,534
Admixed American	0.00167%	59,962
Remaining individualsnot grpmax-eligible	0.0016%	62,412
European (non-Finnish)	0.00144%	69,401

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.Arg52Trp
Coding: c.154C>T
MANE Select: NM_199242
dbSNP: rs930596937
Type: single nucleotide variant
Location: chr17:75843266 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hemophagocytic lymphohistiocytosis 3

Similar variants

UNC13D p.Arg52Gln 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-arg52trp (accessed [today's date]).

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