Is C8B p.Thr220Lys (c.659C>A) pathogenic?

C8B p.Thr220Lys (c.659C>A) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-12-03). AlphaMissense: likely benign (0.1459); Rare (popmax 0.145%, sas); Associated with Inborn genetic diseases.

What condition is associated with C8B p.Thr220Lys (c.659C>A)?

C8B p.Thr220Lys (c.659C>A) is associated with Inborn genetic diseases, type II complement component 8 deficiency (ClinVar).

How common is C8B p.Thr220Lys (c.659C>A) in the general population?

C8B p.Thr220Lys (c.659C>A) is rare (popmax 0.145%, sas) (gnomAD).

What do computational predictors say about C8B p.Thr220Lys (c.659C>A)?

AlphaMissense predicts likely benign (score 0.1459) — an in-silico prediction, not a clinical call.

C8B p.Thr220Lys

c.659C>A · rs374321085 · VCV1511289

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1459 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.145%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1459	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -4.74	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 0.28	GERP -3.9, phastCons 0.023
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	11.31	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 0.145% South Asian · 132/91,080 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.00855% 138/1,614,054 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.145%	690
Middle Eastern	0.0167%	5,996
Remaining individualsnot grpmax-eligible	0.008%	12,500

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.Thr220Lys
Coding: c.659C>A
MANE Select: NM_000066
dbSNP: rs374321085
Type: single nucleotide variant
Location: chr1:56952055 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 220: a UniProt-annotated variant site (in c8d2); a β-strand; the macpf domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type II complement component 8 deficiency

Similar variants

C8B p.Thr220= Likely benign ★★ same residue
C8B p.Thr220Met 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.Ala21Thr Uncertain significance ★★ ⚠ same condition
C8B p.Ala446Val 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-thr220lys (accessed [today's date]).

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