Is UNC13D p.Arg11Pro (c.32G>C) pathogenic?

UNC13D p.Arg11Pro (c.32G>C) is classified Uncertain significance in UNC13D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.1844); Rare (popmax 0.182%, mid); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Arg11Pro (c.32G>C)?

UNC13D p.Arg11Pro (c.32G>C) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg11Pro (c.32G>C) in the general population?

UNC13D p.Arg11Pro (c.32G>C) is rare (popmax 0.182%, 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.Arg11Pro (c.32G>C)?

AlphaMissense predicts likely benign (score 0.1844) — an in-silico prediction, not a clinical call.

UNC13D p.Arg11Pro

c.32G>C · rs574927621 · VCV533101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1844 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial hemophagocytic lymphohistiocytosis 3

Computational evidence

Protein change
AlphaMissense	0.1844	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -5.60	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 4.6	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	24.7	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 0.182% Middle Eastern · 11/6,054 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0788%

Overall 0.00626% 101/1,612,520 alleles · rare exomes 93/1,460,168 · genomes 8/152,352 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	550
South Asian	0.0176%	5,688
Admixed American	0.0117%	8,567
Remaining individualsnot grpmax-eligible	0.0096%	10,414
European (non-Finnish)	0.00517%	19,341

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.Arg11Pro
Coding: c.32G>C
MANE Select: NM_199242
dbSNP: rs574927621
Type: single nucleotide variant
Location: chr17:75844306 (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.Arg11Cys Uncertain significance ★ ⚠ same residue
UNC13D p.Arg11His Uncertain significance ★ ⚠ 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-arg11pro (accessed [today's date]).

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