Is C8B p.Thr445Met (c.1334C>T) pathogenic?

C8B p.Thr445Met (c.1334C>T) is classified Uncertain significance in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-29). AlphaMissense: likely benign (0.169); Ultra-rare (popmax 0.0121%, sas).

How common is C8B p.Thr445Met (c.1334C>T) in the general population?

C8B p.Thr445Met (c.1334C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about C8B p.Thr445Met (c.1334C>T)?

AlphaMissense predicts likely benign (score 0.169) — an in-silico prediction, not a clinical call.

C8B p.Thr445Met

c.1334C>T · rs138837336 · VCV1934062

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.169 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.169	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	21.8	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 0.0121% South Asian · 11/91,070 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00266% 43/1,613,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
African / African-American	0.0107%	9,360
Finnishnot grpmax-eligible	0.00469%	21,338
Admixed American	0.00333%	29,995
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.00144%	69,412

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.Thr445Met
Coding: c.1334C>T
MANE Select: NM_000066
dbSNP: rs138837336
Type: single nucleotide variant
Location: chr1:56940913 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 445: a UniProt-annotated variant site (in c8d2); the macpf domain

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

Similar variants

C8B p.Thr445= Likely benign ★ 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-thr445met (accessed [today's date]).

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