Is C6 p.Arg48Lys (c.143G>A) pathogenic?

C6 p.Arg48Lys (c.143G>A) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-22). AlphaMissense: ambiguous (0.525); Ultra-rare (popmax 0.0365%, nfe); Associated with complement component 6 deficiency.

What condition is associated with C6 p.Arg48Lys (c.143G>A)?

C6 p.Arg48Lys (c.143G>A) is associated with complement component 6 deficiency (ClinVar).

How common is C6 p.Arg48Lys (c.143G>A) in the general population?

C6 p.Arg48Lys (c.143G>A) is ultra-rare (popmax 0.0365%, nfe) (gnomAD).

What do computational predictors say about C6 p.Arg48Lys (c.143G>A)?

AlphaMissense predicts ambiguous (score 0.525) — an in-silico prediction, not a clinical call.

C6 p.Arg48Lys

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.143G>A · rs145422926 · VCV996839

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.525 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0365%, nfe)

Conditions

complement component 6 deficiency

Computational evidence

Protein change
AlphaMissense	0.525	ambiguous
REVEL	0.443	indeterminate
SaProt	LLR -11.06	damaging
Splicing
SpliceAI	Δ0.89	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.70	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 0.96, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	28.3	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 0.0365% European (non-Finnish) · 431/1,179,920 alleles

Filtering AF 0.0337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.0289% 467/1,613,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0365%	2,738
Middle Eastern	0.0332%	3,014
Remaining individualsnot grpmax-eligible	0.0288%	3,470
Admixed American	0.0167%	6,001
South Asian	0.00439%	22,769
African / African-American	0.00267%	37,455

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: C6
Protein: p.Arg48Lys
Coding: c.143G>A
MANE Select: NM_000065
dbSNP: rs145422926
Type: single nucleotide variant
Location: chr5:41203088 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 48: a disulfide bond; the tsp type-1 1 domain; a β-strand

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 6 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Arg606Ter Pathogenic ★★ same condition
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Arg407Cys Uncertain significance ★★ same condition
C6 p.Arg701Trp Uncertain significance ★★ ⚠ same condition
C6 p.Asp667His Uncertain significance ★★ ⚠ same condition
C6 p.Gly643Arg 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/c6-p-arg48lys (accessed [today's date]).

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