Is UNC13D p.Ala995Pro (c.2983G>C) pathogenic?

UNC13D p.Ala995Pro (c.2983G>C) is classified Conflicting classifications of pathogenicity in UNC13D (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.081); Rare (popmax 0.171%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with UNC13D p.Ala995Pro (c.2983G>C)?

UNC13D p.Ala995Pro (c.2983G>C) is associated with autoinflammatory syndrome, familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Ala995Pro (c.2983G>C) in the general population?

UNC13D p.Ala995Pro (c.2983G>C) is rare (popmax 0.171%, nfe) (gnomAD).

What do computational predictors say about UNC13D p.Ala995Pro (c.2983G>C)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

UNC13D p.Ala995Pro

c.2983G>C · rs138760432 · VCV464457

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.171%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -3.75	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 1.4	phastCons 0.97
Regional constraint	o/e 1.01	unconstrained · MANE · 8,134 bp · p 0.68 · regional, not allelic
Overall
CADD	9.131	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 0.171% European (non-Finnish) · 2,020/1,179,566 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.162%

Overall 0.138% 2,216/1,605,018 alleles · rare exomes 2,063/1,452,640 · genomes 153/152,378 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.284%	352
European (non-Finnish)grpmax	0.171%	584
Amishnot grpmax-eligible	0.11%	910
Remaining individualsnot grpmax-eligible	0.103%	974
Admixed American	0.03%	3,332
African / African-American	0.0253%	3,950
Finnishnot grpmax-eligible	0.0178%	5,618

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala995Pro
Coding: c.2983G>C
MANE Select: NM_199242
dbSNP: rs138760432
Type: single nucleotide variant
Location: chr17:75828955 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 995: the c2 2 domain

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: familial hemophagocytic lymphohistiocytosis 3

Similar variants

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
UNC13D c.2447+2T>C 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-ala995pro (accessed [today's date]).

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