Is UNC13D p.Pro716Ser (c.2146C>T) pathogenic?

UNC13D p.Pro716Ser (c.2146C>T) is classified Uncertain significance in UNC13D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-02). AlphaMissense: ambiguous (0.5621); Ultra-rare (popmax 0.0207%, sas); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Pro716Ser (c.2146C>T)?

UNC13D p.Pro716Ser (c.2146C>T) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Pro716Ser (c.2146C>T) in the general population?

UNC13D p.Pro716Ser (c.2146C>T) is ultra-rare (popmax 0.0207%, sas) (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.Pro716Ser (c.2146C>T)?

AlphaMissense predicts ambiguous (score 0.5621) — an in-silico prediction, not a clinical call.

UNC13D p.Pro716Ser

c.2146C>T · rs774476484 · VCV1499017

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0207%, sas)

Conditions

familial hemophagocytic lymphohistiocytosis 3

Computational evidence

Protein change
AlphaMissense	0.5621	ambiguous
REVEL	0.399	indeterminate
SaProt	LLR -10.78	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 8,134 bp · p 0.68 · regional, not allelic
Overall
CADD	24.8	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 0.0207% South Asian · 18/86,794 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.00498% 78/1,565,954 alleles · ultra-rare exomes 72/1,413,724 · genomes 6/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0207%	4,822
Ashkenazi Jewishnot grpmax-eligible	0.0104%	9,617
European (non-Finnish)	0.00466%	21,438
Remaining individualsnot grpmax-eligible	0.00329%	30,409
African / African-American	0.00135%	73,926

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.Pro716Ser
Coding: c.2146C>T
MANE Select: NM_199242
dbSNP: rs774476484
Type: single nucleotide variant
Location: chr17:75834477 (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.Pro716= Likely benign ★ 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-pro716ser (accessed [today's date]).

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