Is C4B p.Val909Ala (c.2726T>C) pathogenic?

C4B p.Val909Ala (c.2726T>C) is classified Uncertain significance in C4B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: likely benign (0.159); Very rare (popmax 0.000342%).

How common is C4B p.Val909Ala (c.2726T>C) in the general population?

C4B p.Val909Ala (c.2726T>C) is very rare (popmax 0.000342%) (gnomAD).

What do computational predictors say about C4B p.Val909Ala (c.2726T>C)?

AlphaMissense predicts likely benign (score 0.159) — an in-silico prediction, not a clinical call.

C4B p.Val909Ala

c.2726T>C · rs1775670727 · VCV3136008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000342%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.159	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.43	acceptor loss, 11 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Overall
CADD	22.3	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 0.000342%

Overall 0.000342% 2/585,550 alleles · very rare

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: C4B
Protein: p.Val909Ala
Coding: c.2726T>C
MANE Select: NM_007293 · reported on NM_001002029
dbSNP: rs1775670727
Type: single nucleotide variant
Location: chr6:32027369 (GRCh38)
Structure: AlphaFold pLDDT 83.56 · 12 PDB
Residue 909: a β-strand

Full C4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C4A c.2944+55T>C Benign/Likely benign ★★ same type
C4A p.Asp1073Gly Benign/Likely benign ★★ same type
C4A p.Pro1120Thr Likely benign ★★ same type
C4B p.Ser1176Asn Benign ★★ ⚠ same type
C4B p.Thr907Ala Benign/Likely benign ★★ same type
C4B c.3230+1G>A Likely pathogenic ★ same type
C4B c.3676+1G>A Likely pathogenic ★ same type
C4A p.Ala1062Val 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/c4b-p-val909ala (accessed [today's date]).

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