Is C8B p.Arg338Cys (c.1012C>T) pathogenic?

C8B p.Arg338Cys (c.1012C>T) is classified Uncertain significance in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: ambiguous (0.3401); Rare (popmax 0.156%, afr).

How common is C8B p.Arg338Cys (c.1012C>T) in the general population?

C8B p.Arg338Cys (c.1012C>T) is rare (popmax 0.156%, afr) (gnomAD).

What do computational predictors say about C8B p.Arg338Cys (c.1012C>T)?

AlphaMissense predicts ambiguous (score 0.3401) — an in-silico prediction, not a clinical call.

C8B p.Arg338Cys

c.1012C>T · rs141136423 · VCV1025731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3401 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.156%, afr)

Computational evidence

Protein change
AlphaMissense	0.3401	ambiguous
REVEL	0.588	indeterminate
SaProt	LLR -10.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	27.6	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 0.156% African / African-American · 117/75,000 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.0208% 336/1,614,040 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.156%	641
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Admixed American	0.0217%	4,616
European (non-Finnish)	0.0143%	6,982
South Asian	0.00988%	10,119
East Asian	0.00446%	22,433
Finnishnot grpmax-eligible	0.00156%	64,018

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.Arg338Cys
Coding: c.1012C>T
MANE Select: NM_000066
dbSNP: rs141136423
Type: single nucleotide variant
Location: chr1:56945914 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 338: 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

Similar variants

C8B p.Arg338His Uncertain significance ★ ⚠ same residue
C8B p.Arg338= Likely benign ★ same residue
C8B p.Arg284Ter Pathogenic ★★ same type
C8B p.Arg428Ter Pathogenic ★★ same type
C8B p.Cys508Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Gln91Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Trp9Ter Pathogenic ★★ same type
C8B p.Ala21Thr Uncertain significance ★★ ⚠ 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/c8b-p-arg338cys (accessed [today's date]).

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