Is C8B p.Trp452Ser (c.1355G>C) pathogenic?

C8B p.Trp452Ser (c.1355G>C) is classified Benign/Likely benign in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.9533); Rare (popmax 0.613%, eas); Associated with type II complement component 8 deficiency.

What condition is associated with C8B p.Trp452Ser (c.1355G>C)?

C8B p.Trp452Ser (c.1355G>C) is associated with type II complement component 8 deficiency (ClinVar).

How common is C8B p.Trp452Ser (c.1355G>C) in the general population?

C8B p.Trp452Ser (c.1355G>C) is rare (popmax 0.613%, eas) (gnomAD).

What do computational predictors say about C8B p.Trp452Ser (c.1355G>C)?

AlphaMissense predicts likely pathogenic (score 0.9533) — an in-silico prediction, not a clinical call.

C8B p.Trp452Ser

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.1355G>C · rs200077558 · VCV1167718

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9533 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.613%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type II complement component 8 deficiency

Computational evidence

Protein change
AlphaMissense	0.9533	likely pathogenic · top 3% in C8B
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -9.62	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	29.4	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 0.613% East Asian · 275/44,866 alleles

Filtering AF 0.553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.53%

Overall 0.0193% 312/1,614,028 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.613%	163
Remaining individualsnot grpmax-eligible	0.0336%	2,977
European (non-Finnish)	0.00127%	78,666
South Asian	0.0011%	91,070

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: C8B
Protein: p.Trp452Ser
Coding: c.1355G>C
MANE Select: NM_000066
dbSNP: rs200077558
Type: single nucleotide variant
Location: chr1:56940892 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 452: a UniProt-annotated variant site (in c8d2); an α-helix; the macpf domain

Full C8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

type II complement component 8 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

C8B p.Trp452Ter Pathogenic ★ same residue
C8B p.Trp452Gly Uncertain significance ★ ⚠ same residue
C8B p.Arg284Ter Pathogenic ★★ same condition
C8B p.Arg428Ter Pathogenic ★★ same condition
C8B p.Gln91Ter Pathogenic/Likely pathogenic ★★ same condition
C8B p.Trp9Ter Pathogenic ★★ same condition
C8B p.Ala461Ser Uncertain significance ★★ ⚠ same condition
C8B p.Ala480Thr 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/c8b-p-trp452ser (accessed [today's date]).

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