Is UNC13D p.Val210fs (c.627del) pathogenic?

UNC13D p.Val210fs (c.627del) is classified Pathogenic in UNC13D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-20). Ultra-rare (popmax 0.0165%, mid); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Val210fs (c.627del)?

UNC13D p.Val210fs (c.627del) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Val210fs (c.627del) in the general population?

UNC13D p.Val210fs (c.627del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

UNC13D p.Val210fs

c.627del · rs755619812 · VCV2138108

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

familial hemophagocytic lymphohistiocytosis 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 32
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	phastCons 1
Overall
CADD	1.49	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,614,060 alleles · ultra-rare exomes 5/1,461,750 · genomes 2/152,310 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000424%	236,008

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.Val210fs
Coding: c.627del
MANE Select: NM_199242
dbSNP: rs755619812
Type: Deletion
Location: chr17:75840818 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 210: the c2 1 domain

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

Disease context

familial hemophagocytic lymphohistiocytosis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

UNC13D p.Val210Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
UNC13D p.Val210Leu Uncertain significance ★ ⚠ same residue
UNC13D p.Arg610_Gln613del Pathogenic ★★ same condition
UNC13D p.Arg782fs Pathogenic ★★ same condition
UNC13D p.Asn1050fs Likely pathogenic ★★ same condition
UNC13D p.Asp236fs Pathogenic ★★ same condition
UNC13D p.Cys255fs Pathogenic ★★ same condition
UNC13D p.Leu54fs 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-val210fs (accessed [today's date]).

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