Is C8B p.Ala455Val (c.1364C>T) pathogenic?

C8B p.Ala455Val (c.1364C>T) is classified Uncertain significance in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-06). AlphaMissense: ambiguous (0.3927); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with C8B p.Ala455Val (c.1364C>T)?

C8B p.Ala455Val (c.1364C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C8B p.Ala455Val (c.1364C>T) in the general population?

C8B p.Ala455Val (c.1364C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about C8B p.Ala455Val (c.1364C>T)?

AlphaMissense predicts ambiguous (score 0.3927) — an in-silico prediction, not a clinical call.

C8B p.Ala455Val

c.1364C>T · rs41285942 · VCV2474072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3927	ambiguous
REVEL	0.655	pathogenic-leaning
SaProt	LLR -9.97	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	23.8	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 0.00223% East Asian · 1/44,858 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,030 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,858
European (non-Finnish)	0.000508%	196,668

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.Ala455Val
Coding: c.1364C>T
MANE Select: NM_000066
dbSNP: rs41285942
Type: single nucleotide variant
Location: chr1:56940883 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 455: 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

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

Similar variants

C8B p.Ala455Thr Uncertain significance ★ ⚠ same residue
C8B p.Ala455= Likely benign ★ same residue
C8B p.Ala21Thr Uncertain significance ★★ ⚠ same condition
C8B p.Ala446Val Uncertain significance ★★ ⚠ same condition
C8B p.Arg136Cys Uncertain significance ★★ ⚠ same condition
C8B p.Arg136His Uncertain significance ★★ ⚠ same condition
C8B p.Arg156Gly Uncertain significance ★★ ⚠ same condition
C8B p.Arg296Cys 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-ala455val (accessed [today's date]).

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