Is C4B p.Ala1286Val (c.3857C>T) pathogenic?

C4B p.Ala1286Val (c.3857C>T) is classified Uncertain significance in C4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1875); Ultra-rare (popmax 0.0121%, sas).

How common is C4B p.Ala1286Val (c.3857C>T) in the general population?

C4B p.Ala1286Val (c.3857C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about C4B p.Ala1286Val (c.3857C>T)?

AlphaMissense predicts likely benign (score 0.1875) — an in-silico prediction, not a clinical call.

C4B p.Ala1286Val

c.3857C>T · VCV3994069

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1875 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1875	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -7.46	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 7.5	GERP 1.8, phastCons 1
Overall
CADD	23.9	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 · 11/90,862 alleles

Filtering AF 0.00678% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00523%

Overall 0.00347% 56/1,612,222 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,260
East Asian	0.00898%	11,131
African / African-American	0.004%	25,021
Admixed American	0.00333%	30,012
European (non-Finnish)	0.00297%	33,710
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Ala1286Val
Coding: c.3857C>T
MANE Select: NM_007293 · reported on NM_001002029
Type: single nucleotide variant
Location: chr6:32029746 (GRCh38)
Structure: AlphaFold pLDDT 83.56 · 12 PDB
Residue 1286: an α-helix; a UniProt-annotated variant site (in allotype c4a1, allotype c4a3a, allotype c4a6)

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

Similar variants

C4A p.Ser1286Ala Benign same residue
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

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-ala1286val (accessed [today's date]).

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