Is UNC13D p.Arg993His (c.2978G>A) pathogenic?

UNC13D p.Arg993His (c.2978G>A) is classified Uncertain significance in UNC13D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.0947); Ultra-rare (popmax 0.0357%, eas); Associated with Inborn genetic diseases.

What condition is associated with UNC13D p.Arg993His (c.2978G>A)?

UNC13D p.Arg993His (c.2978G>A) is associated with Inborn genetic diseases, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg993His (c.2978G>A) in the general population?

UNC13D p.Arg993His (c.2978G>A) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

What do computational predictors say about UNC13D p.Arg993His (c.2978G>A)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

UNC13D p.Arg993His

c.2978G>A · VCV3466010

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3
Regional constraint	o/e 1.01	unconstrained · MANE · 8,134 bp · p 0.68 · regional, not allelic
Overall
CADD	7.083	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 0.0357% East Asian · 16/44,876 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00262% 42/1,604,404 alleles · ultra-rare exomes 38/1,452,164 · genomes 4/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,805
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,548
European (non-Finnish)	0.00187%	53,614
Remaining individualsnot grpmax-eligible	0.00161%	62,304
African / African-American	0.00133%	74,910
South Asian	0.0011%	90,980

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.Arg993His
Coding: c.2978G>A
MANE Select: NM_199242
Type: single nucleotide variant
Location: chr17:75828960 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 993: the c2 2 domain

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.Arg993Cys Uncertain significance ★ ⚠ same residue
UNC13D p.Arg993Leu Uncertain significance ★ ⚠ same residue
UNC13D p.Arg993Ser Uncertain significance ★ ⚠ same residue
UNC13D p.Arg993= 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

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-arg993his (accessed [today's date]).

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