Is C8B p.Val536Asp (c.1607T>A) pathogenic?

C8B p.Val536Asp (c.1607T>A) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.1075); Rare (popmax 0.175%, nfe).

How common is C8B p.Val536Asp (c.1607T>A) in the general population?

C8B p.Val536Asp (c.1607T>A) is rare (popmax 0.175%, nfe) (gnomAD).

What do computational predictors say about C8B p.Val536Asp (c.1607T>A)?

AlphaMissense predicts likely benign (score 0.1075) — an in-silico prediction, not a clinical call.

C8B p.Val536Asp

c.1607T>A · rs143417649 · VCV1366009

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1075 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.175%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1075	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.55	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 7.3	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	22.2	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 0.175% European (non-Finnish) · 2,062/1,177,456 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.166%

Overall 0.139% 2,242/1,610,386 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.175%	571
Remaining individualsnot grpmax-eligible	0.131%	761
South Asian	0.0703%	1,422
Middle Eastern	0.033%	3,026
African / African-American	0.0214%	4,683
Admixed American	0.0167%	5,995
Finnishnot grpmax-eligible	0.0079%	12,663
East Asian	0.00223%	44,818

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.Val536Asp
Coding: c.1607T>A
MANE Select: NM_000066
dbSNP: rs143417649
Type: single nucleotide variant
Location: chr1:56931824 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 536: a disulfide bond; a UniProt-annotated variant site (in c8d2); a β-strand

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

Similar variants

C8B p.Val536Ile Conflicting classifications of pathogenicity ★ ⚠ 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
C8B p.Ala446Val 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-val536asp (accessed [today's date]).

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