Is UNC13D p.Pro485Arg (c.1454C>G) pathogenic?

UNC13D p.Pro485Arg (c.1454C>G) is classified Uncertain significance in UNC13D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-22). AlphaMissense: likely benign (0.0817); Very rare (popmax 0.00102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with UNC13D p.Pro485Arg (c.1454C>G)?

UNC13D p.Pro485Arg (c.1454C>G) is associated with Inborn genetic diseases (ClinVar).

How common is UNC13D p.Pro485Arg (c.1454C>G) in the general population?

UNC13D p.Pro485Arg (c.1454C>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about UNC13D p.Pro485Arg (c.1454C>G)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

UNC13D p.Pro485Arg

c.1454C>G · VCV3466007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.69	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 5	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 8,134 bp · p 0.68 · regional, not allelic
Overall
CADD	17.49	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 0.00102% European (non-Finnish) · 12/1,180,036 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,613,228 alleles · very rare exomes 10/1,460,996 · genomes 2/152,232 · 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.Pro485Arg
Coding: c.1454C>G
MANE Select: NM_199242
Type: single nucleotide variant
Location: chr17:75836102 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 485: the 'interaction with rab27a' region

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

Similar variants

UNC13D p.Pro485Leu Uncertain significance ★★ ⚠ same residue
UNC13D p.Pro485= Likely benign ★ same residue
UNC13D p.Ala1048Thr Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala1085Val Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala339Thr Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala581Ser Uncertain significance ★★ ⚠ same condition
UNC13D p.Ala604Val Uncertain significance ★★ same condition
UNC13D p.Ala638Val Uncertain significance ★★ ⚠ 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-pro485arg (accessed [today's date]).

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