Is C8B p.Pro12Leu (c.35C>T) pathogenic?

C8B p.Pro12Leu (c.35C>T) is classified Conflicting classifications of pathogenicity in C8B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-23). AlphaMissense: likely benign (0.0803); Ultra-rare (popmax 0.0121%, sas); Associated with Inborn genetic diseases.

What condition is associated with C8B p.Pro12Leu (c.35C>T)?

C8B p.Pro12Leu (c.35C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C8B p.Pro12Leu (c.35C>T) in the general population?

C8B p.Pro12Leu (c.35C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about C8B p.Pro12Leu (c.35C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

C8B p.Pro12Leu

c.35C>T · rs760472969 · VCV1914175

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -6.19	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 -2.6	GERP -4.7
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	0.125	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 0.0121% South Asian · 11/91,050 alleles

Filtering AF 0.00677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00186% 30/1,613,864 alleles · ultra-rare exomes 22/1,461,838 · genomes 8/152,026 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,277
Admixed American	0.01%	9,999
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00134%	74,874
European (non-Finnish)	0.000932%	107,274

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.Pro12Leu
Coding: c.35C>T
MANE Select: NM_000066
dbSNP: rs760472969
Type: single nucleotide variant
Location: chr1:56965914 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB

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.Pro12= 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
C8B p.Arg296His 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-pro12leu (accessed [today's date]).

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