Is UNC13D p.Arg172Pro (c.515G>C) pathogenic?

UNC13D p.Arg172Pro (c.515G>C) is classified Uncertain significance in UNC13D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). AlphaMissense: likely pathogenic (0.8211); Very rare (popmax 0.000254%, nfe); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Arg172Pro (c.515G>C)?

UNC13D p.Arg172Pro (c.515G>C) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg172Pro (c.515G>C) in the general population?

UNC13D p.Arg172Pro (c.515G>C) is very rare (popmax 0.000254%, nfe) (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.Arg172Pro (c.515G>C)?

AlphaMissense predicts likely pathogenic (score 0.8211) — an in-silico prediction, not a clinical call.

UNC13D p.Arg172Pro

c.515G>C · rs769659694 · VCV1471717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8211 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hemophagocytic lymphohistiocytosis 3

Computational evidence

Protein change
AlphaMissense	0.8211	likely pathogenic
REVEL	0.289	benign-leaning
SaProt	LLR -14.02	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	28.3	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 0.000254% European (non-Finnish) · 3/1,179,896 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,298 alleles · very rare exomes 3/1,460,984 · genomes 0/152,314 · joint denominator

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.Arg172Pro
Coding: c.515G>C
MANE Select: NM_199242
dbSNP: rs769659694
Type: single nucleotide variant
Location: chr17:75842487 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 172: the c2 1 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 p.Arg172Cys Uncertain significance ★★ ⚠ same residue
UNC13D p.Arg172His Uncertain significance ★ ⚠ same residue
UNC13D p.Arg172Ser Uncertain significance ★ ⚠ same residue
UNC13D p.Arg172fs Likely 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

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-arg172pro (accessed [today's date]).

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