Is UNC13D p.Arg607Pro (c.1820G>C) pathogenic?

UNC13D p.Arg607Pro (c.1820G>C) is classified Conflicting classifications of pathogenicity in UNC13D (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.9867); Ultra-rare (popmax 0.0459%, nfe); Associated with UNC13D-related disorder.

What condition is associated with UNC13D p.Arg607Pro (c.1820G>C)?

UNC13D p.Arg607Pro (c.1820G>C) is associated with UNC13D-related disorder, familial hemophagocytic lymphohistiocytosis 3, hereditary hemophagocytic lymphohistiocytosis (ClinVar).

How common is UNC13D p.Arg607Pro (c.1820G>C) in the general population?

UNC13D p.Arg607Pro (c.1820G>C) is ultra-rare (popmax 0.0459%, nfe) (gnomAD).

What do computational predictors say about UNC13D p.Arg607Pro (c.1820G>C)?

AlphaMissense predicts likely pathogenic (score 0.9867) — an in-silico prediction, not a clinical call.

UNC13D p.Arg607Pro

c.1820G>C · rs377293829 · VCV632290

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0459%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

UNC13D-related disorder

Computational evidence

Protein change
AlphaMissense	0.9867	likely pathogenic · top 1% in UNC13D
REVEL	0.684	pathogenic-leaning
SaProt	LLR -16.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.89 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 8,134 bp · p 0.68 · regional, not allelic
Overall
CADD	28.0	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 0.0459% European (non-Finnish) · 541/1,179,838 alleles

Filtering AF 0.0426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0414%

Overall 0.0352% 568/1,612,832 alleles · ultra-rare exomes 541/1,460,466 · genomes 27/152,366 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0459%	2,181
African / African-American	0.0213%	4,691
Middle Eastern	0.0168%	5,968
Remaining individualsnot grpmax-eligible	0.0128%	7,806
Admixed American	0.00167%	59,976
South Asian	0.0011%	91,046

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.Arg607Pro
Coding: c.1820G>C
MANE Select: NM_199242
dbSNP: rs377293829
Type: single nucleotide variant
Location: chr17:75835437 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 607: the mhd1 domain

Full UNC13D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

UNC13D-related disorder

Also linked: familial hemophagocytic lymphohistiocytosis 3 hereditary hemophagocytic lymphohistiocytosis autoinflammatory syndrome

Similar variants

UNC13D p.Arg607Gln Uncertain significance ★★ same residue
UNC13D p.Arg607Gly Uncertain significance ★ ⚠ same residue
UNC13D p.Arg607Trp Uncertain significance ★ same residue
UNC13D p.Arg607= 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-arg607pro (accessed [today's date]).

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