Is C8B p.Ala461Ser (c.1381G>T) pathogenic?

C8B p.Ala461Ser (c.1381G>T) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-10). AlphaMissense: likely benign (0.0806); Very rare (popmax 0.0011%, sas); Associated with type II complement component 8 deficiency.

What condition is associated with C8B p.Ala461Ser (c.1381G>T)?

C8B p.Ala461Ser (c.1381G>T) is associated with type II complement component 8 deficiency (ClinVar).

How common is C8B p.Ala461Ser (c.1381G>T) in the general population?

C8B p.Ala461Ser (c.1381G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about C8B p.Ala461Ser (c.1381G>T)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

C8B p.Ala461Ser

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.1381G>T · rs2101385310 · VCV2159959

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type II complement component 8 deficiency

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.7, phastCons 0.52
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	18.92	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,066 alleles

Overall 0.000205% 3/1,461,848 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asiangrpmax	0.0011%	91,066
European (non-Finnish)	8.47e-05%	1,179,988

Remaining individuals 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: C8B
Protein: p.Ala461Ser
Coding: c.1381G>T
MANE Select: NM_000066
dbSNP: rs2101385310
Type: single nucleotide variant
Location: chr1:56940866 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 461: a UniProt-annotated variant site (in c8d2); the macpf domain; a β-strand

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.Ala461Gly Uncertain significance ★ ⚠ same residue
C8B p.Ala461= Likely benign 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.Ala480Thr Uncertain significance ★★ ⚠ same condition
C8B p.Arg136His 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-ala461ser (accessed [today's date]).

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