Is C4B p.Leu1179Phe (c.3537G>C) pathogenic?

C4B p.Leu1179Phe (c.3537G>C) is classified Uncertain significance in C4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.5741); Very rare (popmax 0.00103%, nfe).

How common is C4B p.Leu1179Phe (c.3537G>C) in the general population?

C4B p.Leu1179Phe (c.3537G>C) is very rare (popmax 0.00103%, nfe) (gnomAD).

What do computational predictors say about C4B p.Leu1179Phe (c.3537G>C)?

AlphaMissense predicts likely pathogenic (score 0.5741) — an in-silico prediction, not a clinical call.

C4B p.Leu1179Phe

c.3537G>C · VCV4647298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00103%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5741	likely pathogenic
REVEL	0.44	indeterminate
SaProt	LLR -14.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP -0.92, phastCons 1
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00103% European (non-Finnish) · 12/1,163,300 alleles

Filtering AF 0.00055% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000434%

Overall 0.000942% 15/1,591,688 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00486%	20,579
European (non-Finnish)grpmax	0.00103%	96,941

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu1179Phe
Coding: c.3537G>C
MANE Select: NM_007293 · reported on NM_001002029
Type: single nucleotide variant
Location: chr6:32029199 (GRCh38)
Structure: AlphaFold pLDDT 83.56 · 12 PDB
Residue 1179: an α-helix

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

Similar variants

C4B p.Leu1179Trp Uncertain significance ★ ⚠ 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-leu1179phe (accessed [today's date]).

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