Is C6 p.Asp667His (c.1999G>C) pathogenic?

C6 p.Asp667His (c.1999G>C) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-15). AlphaMissense: likely benign (0.2418); Ultra-rare (popmax 0.0921%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Asp667His (c.1999G>C)?

C6 p.Asp667His (c.1999G>C) is associated with Inborn genetic diseases, complement component 6 deficiency (ClinVar).

How common is C6 p.Asp667His (c.1999G>C) in the general population?

C6 p.Asp667His (c.1999G>C) is ultra-rare (popmax 0.0921%, nfe) (gnomAD).

What do computational predictors say about C6 p.Asp667His (c.1999G>C)?

AlphaMissense predicts likely benign (score 0.2418) — an in-silico prediction, not a clinical call.

C6 p.Asp667His

c.1999G>C · rs184169749 · VCV809752

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2418 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0921%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2418	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -7.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP -1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	17.5	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 0.0921% European (non-Finnish) · 1,087/1,179,672 alleles

Filtering AF 0.0875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0857%

Overall 0.0728% 1,174/1,613,666 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0921%	1,085
Admixed American	0.0684%	1,463
Remaining individualsnot grpmax-eligible	0.056%	1,785
African / African-American	0.0147%	6,820

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.Asp667His
Coding: c.1999G>C
MANE Select: NM_000065
dbSNP: rs184169749
Type: single nucleotide variant
Location: chr5:41155074 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 667: the sushi 1 domain; the 'ccp 1' region; a β-strand; the 'c5b-binding domain' region; a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: complement component 6 deficiency

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.Ala396Gly Uncertain significance ★★ ⚠ same condition
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same condition
C6 p.Ala500Ser Uncertain significance ★★ ⚠ same condition
C6 p.Arg108His 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-asp667his (accessed [today's date]).

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