Is UNC13D p.Arg293Cys (c.877C>T) pathogenic?

UNC13D p.Arg293Cys (c.877C>T) is classified Uncertain significance in UNC13D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-07). AlphaMissense: likely benign (0.1137); Ultra-rare (popmax 0.011%, sas); Associated with Inborn genetic diseases.

What condition is associated with UNC13D p.Arg293Cys (c.877C>T)?

UNC13D p.Arg293Cys (c.877C>T) is associated with Inborn genetic diseases, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg293Cys (c.877C>T) in the general population?

UNC13D p.Arg293Cys (c.877C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about UNC13D p.Arg293Cys (c.877C>T)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

UNC13D p.Arg293Cys

c.877C>T · rs778801174 · VCV2054038

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	32.0	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 0.011% South Asian · 10/91,034 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00167% 27/1,612,850 alleles · ultra-rare exomes 26/1,460,692 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,103
East Asian	0.00446%	22,432
Remaining individualsnot grpmax-eligible	0.0016%	62,420
European (non-Finnish)	0.00119%	84,277

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.Arg293Cys
Coding: c.877C>T
MANE Select: NM_199242
dbSNP: rs778801174
Type: single nucleotide variant
Location: chr17:75840092 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 293: the 'interaction with rab27a' region

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.Arg293fs 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-arg293cys (accessed [today's date]).

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