Is C8B p.Pro444Leu (c.1331C>T) pathogenic?

C8B p.Pro444Leu (c.1331C>T) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-10). AlphaMissense: ambiguous (0.5565); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with C8B p.Pro444Leu (c.1331C>T)?

C8B p.Pro444Leu (c.1331C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C8B p.Pro444Leu (c.1331C>T) in the general population?

C8B p.Pro444Leu (c.1331C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about C8B p.Pro444Leu (c.1331C>T)?

AlphaMissense predicts ambiguous (score 0.5565) — an in-silico prediction, not a clinical call.

C8B p.Pro444Leu

c.1331C>T · rs371378397 · VCV1409825

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5565 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5565	ambiguous
REVEL	0.708	pathogenic-leaning
SaProt	LLR -6.98	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 9.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	26.5	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00483% 78/1,613,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.01%	9,999
European (non-Finnish)	0.00559%	17,879
African / African-American	0.00267%	37,427
East Asian	0.00223%	44,864
Remaining individualsnot grpmax-eligible	0.0016%	62,482
Finnishnot grpmax-eligible	0.00156%	64,010

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.Pro444Leu
Coding: c.1331C>T
MANE Select: NM_000066
dbSNP: rs371378397
Type: single nucleotide variant
Location: chr1:56940916 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 444: a UniProt-annotated variant site (in c8d2); 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.Pro444= 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-pro444leu (accessed [today's date]).

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