Is C6 p.Arg596Ter (c.1786C>T) pathogenic?

C6 p.Arg596Ter (c.1786C>T) is classified Pathogenic/Likely pathogenic in C6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-23). Very rare (popmax 0.00892%, eas); Associated with complement component 6 deficiency.

What condition is associated with C6 p.Arg596Ter (c.1786C>T)?

C6 p.Arg596Ter (c.1786C>T) is associated with complement component 6 deficiency (ClinVar).

How common is C6 p.Arg596Ter (c.1786C>T) in the general population?

C6 p.Arg596Ter (c.1786C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

C6 p.Arg596Ter

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

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

c.1786C>T · rs142881576 · VCV208565

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

complement component 6 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1, phastCons 0.001
Overall
CADD	35.0	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 0.00892% East Asian · 4/44,846 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00868% 140/1,613,406 alleles · very rare exomes 121/1,461,476 · genomes 19/151,930 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.237%	423
Remaining individualsnot grpmax-eligible	0.0144%	6,942
East Asiangrpmax	0.00892%	11,212
South Asian	0.00439%	22,766
European (non-Finnish)	0.00424%	23,594
African / African-American	0.00267%	37,441
Admixed American	0.00167%	59,916

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: C6
Protein: p.Arg596Ter
Coding: c.1786C>T
MANE Select: NM_000065
dbSNP: rs142881576
Type: single nucleotide variant
Location: chr5:41159152 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 596: a β-strand; the tsp type-1 3 domain

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 6 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C6 p.Arg596Gln Likely benign ★★ same residue
C6 p.Arg606Ter Pathogenic ★★ same condition
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Arg407Cys Uncertain significance ★★ same condition
C6 p.Arg48Lys Uncertain significance ★★ same condition
C6 p.Arg701Trp Uncertain significance ★★ ⚠ same condition
C6 p.Asp667His 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/c6-p-arg596ter (accessed [today's date]).

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