Is C8B p.Arg83Ser (c.249G>T) pathogenic?

C8B p.Arg83Ser (c.249G>T) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-02). AlphaMissense: ambiguous (0.5577); Ultra-rare (popmax 0.0178%, eas); Associated with type II complement component 8 deficiency.

What condition is associated with C8B p.Arg83Ser (c.249G>T)?

C8B p.Arg83Ser (c.249G>T) is associated with type II complement component 8 deficiency (ClinVar).

How common is C8B p.Arg83Ser (c.249G>T) in the general population?

C8B p.Arg83Ser (c.249G>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about C8B p.Arg83Ser (c.249G>T)?

AlphaMissense predicts ambiguous (score 0.5577) — an in-silico prediction, not a clinical call.

C8B p.Arg83Ser

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.249G>T · rs567145070 · VCV2151875

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

type II complement component 8 deficiency

Computational evidence

Protein change
AlphaMissense	0.5577	ambiguous
REVEL	0.182	moderately benign-leaning
SaProt	LLR -11.13	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.55	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.40	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	27.2	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 0.0178% East Asian · 8/44,868 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000991% 16/1,614,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,608
Remaining individualsnot grpmax-eligible	0.0048%	20,833
South Asian	0.0011%	91,068
European (non-Finnish)	0.000339%	295,003

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.Arg83Ser
Coding: c.249G>T
MANE Select: NM_000066
dbSNP: rs567145070
Type: single nucleotide variant
Location: chr1:56960020 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 83: a disulfide bond; a β-strand; the tsp type-1 1 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.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
C8B p.Arg136His Uncertain significance ★★ ⚠ same condition
C8B p.Arg323Trp 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-arg83ser (accessed [today's date]).

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