Is UNC13D p.Val779Met (c.2335G>A) pathogenic?

UNC13D p.Val779Met (c.2335G>A) is classified Conflicting classifications of pathogenicity in UNC13D (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.1088); Rare (popmax 0.494%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with UNC13D p.Val779Met (c.2335G>A)?

UNC13D p.Val779Met (c.2335G>A) is associated with autoinflammatory syndrome, intellectual disability, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Val779Met (c.2335G>A) in the general population?

UNC13D p.Val779Met (c.2335G>A) is rare (popmax 0.494%, nfe) (gnomAD).

What do computational predictors say about UNC13D p.Val779Met (c.2335G>A)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

UNC13D p.Val779Met

c.2335G>A · rs113861754 · VCV403593

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.494%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.27	phastCons 0.015
Regional constraint	o/e 1.01	unconstrained · MANE · 8,134 bp · p 0.68 · regional, not allelic
Overall
CADD	16.45	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 0.494% European (non-Finnish) · 5,833/1,180,024 alleles

Filtering AF 0.484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.479%

Overall 0.416% 6,710/1,613,834 alleles · rare exomes 6,179/1,461,480 · genomes 531/152,354 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.494%	202
Remaining individualsnot grpmax-eligible	0.421%	238
Finnishnot grpmax-eligible	0.331%	302
Ashkenazi Jewishnot grpmax-eligible	0.233%	429
Admixed American	0.227%	441
South Asian	0.147%	680
Middle Eastern	0.115%	866
African / African-American	0.0759%	1,317

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.Val779Met
Coding: c.2335G>A
MANE Select: NM_199242
dbSNP: rs113861754
Type: single nucleotide variant
Location: chr17:75834107 (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

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability familial hemophagocytic lymphohistiocytosis 3

Similar variants

UNC13D p.Val779= 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-val779met (accessed [today's date]).

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