Is C8B p.Pro261Leu (c.782C>T) pathogenic?

C8B p.Pro261Leu (c.782C>T) is classified Benign/Likely benign in C8B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1358); Common (popmax 8.5%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C8B p.Pro261Leu (c.782C>T)?

AlphaMissense predicts likely benign (score 0.1358) — an in-silico prediction, not a clinical call.

C8B p.Pro261Leu

Q: How common is C8B p.Pro261Leu (c.782C>T) in the general population?

C8B p.Pro261Leu (c.782C>T) is common (popmax 8.5%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.782C>T · rs12085435 · VCV1170461

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1358 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.5%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1358	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -5.97	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 -0.1	GERP -4
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	4.393	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 8.5% Middle Eastern · 515/6,062 alleles

Filtering AF 7.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.65%

Overall 5.19% 83,806/1,613,678 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	8.5%	12
African / African-American	6.6%	15
South Asian	6.41%	16
Ashkenazi Jewishnot grpmax-eligible	5.75%	17
European (non-Finnish)	5.36%	19
Remaining individualsnot grpmax-eligible	5.26%	19
Admixed American	3.52%	28
Finnishnot grpmax-eligible	3.4%	29
Amishnot grpmax-eligible	2.19%	46
East Asian	0.0245%	4,078

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.Pro261Leu
Coding: c.782C>T
MANE Select: NM_000066
dbSNP: rs12085435
Type: single nucleotide variant
Location: chr1:56949637 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 261: a UniProt-annotated variant site (in c8d2); a UniProt-annotated variant site (in); the macpf domain

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

Similar variants

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
C8B p.Ala461Ser 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-pro261leu (accessed [today's date]).

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