Is C6 p.Val668Asp (c.2003T>A) pathogenic?

C6 p.Val668Asp (c.2003T>A) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-23). AlphaMissense: likely pathogenic (0.5863); Ultra-rare (popmax 0.0658%, mid); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Val668Asp (c.2003T>A)?

C6 p.Val668Asp (c.2003T>A) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Val668Asp (c.2003T>A) in the general population?

C6 p.Val668Asp (c.2003T>A) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about C6 p.Val668Asp (c.2003T>A)?

AlphaMissense predicts likely pathogenic (score 0.5863) — an in-silico prediction, not a clinical call.

C6 p.Val668Asp

c.2003T>A · rs763461505 · VCV1402720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5863	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -10.89	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -1.1, phastCons 0.025
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	19.35	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 0.0658% Middle Eastern · 4/6,078 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00471% 76/1,613,584 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,520
Remaining individualsnot grpmax-eligible	0.016%	6,245
Admixed American	0.0133%	7,493
Finnishnot grpmax-eligible	0.00781%	12,807
European (non-Finnish)	0.00407%	24,577
South Asian	0.0011%	91,086

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.Val668Asp
Coding: c.2003T>A
MANE Select: NM_000065
dbSNP: rs763461505
Type: single nucleotide variant
Location: chr5:41155070 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 668: 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

Similar variants

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
C6 p.Arg145His Uncertain significance ★★ ⚠ same condition
C6 p.Arg150His Uncertain significance ★★ ⚠ same condition
C6 p.Arg182Gln Uncertain significance ★★ ⚠ same condition
C6 p.Arg356Gln 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-val668asp (accessed [today's date]).

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