Is C8G p.Ser34fs (c.93_99dup) pathogenic?

C8G p.Ser34fs (c.9399dup) is classified Uncertain significance in C8G (ClinVar, Single submitter, 2 submitters; last evaluated 2021-03-30). Ultra-rare (popmax 0.0205%, nfe); Associated with immunodeficiency disease.

What condition is associated with C8G p.Ser34fs (c.93_99dup)?

C8G p.Ser34fs (c.93_99dup) is associated with immunodeficiency disease (ClinVar).

How common is C8G p.Ser34fs (c.93_99dup) in the general population?

C8G p.Ser34fs (c.93_99dup) is ultra-rare (popmax 0.0205%, nfe) (gnomAD).

C8G p.Ser34fs

c.93_99dup · rs758635843 · VCV626069

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0205%, nfe)

Conditions

immunodeficiency disease

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 1 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.074	GERP -2.8
Overall
CADD	17.16	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 0.0205% European (non-Finnish) · 241/1,174,314 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0175%

Overall 0.0157% 251/1,600,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0205%	4,873
Remaining individualsnot grpmax-eligible	0.0145%	6,888
South Asian	0.00112%	89,038

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: C8G
Protein: p.Ser34fs
Coding: c.93_99dup
MANE Select: NM_000606
dbSNP: rs758635843
Type: Duplication
Location: chr9:136945408 (GRCh38)
Gene constraint: LOEUF 1.809 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.06 · 15 PDB
Residue 34: an α-helix

Full C8G gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C8G p.Tyr181His Uncertain significance ★★ ⚠ same condition
C8G c.138+17dup Likely benign ★ same type
C8G c.276-3dup Benign same type

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/c8g-p-ser34fs (accessed [today's date]).

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