Is C6 p.Asp696Asn (c.2086G>A) pathogenic?

C6 p.Asp696Asn (c.2086G>A) is classified Conflicting classifications of pathogenicity in C6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0743); Low-frequency (popmax 1.05%, afr); Associated with Inborn genetic diseases.

What condition is associated with C6 p.Asp696Asn (c.2086G>A)?

C6 p.Asp696Asn (c.2086G>A) is associated with Inborn genetic diseases (ClinVar).

How common is C6 p.Asp696Asn (c.2086G>A) in the general population?

C6 p.Asp696Asn (c.2086G>A) is low-frequency (popmax 1.05%, afr) (gnomAD).

What do computational predictors say about C6 p.Asp696Asn (c.2086G>A)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

C6 p.Asp696Asn

c.2086G>A · rs78888823 · VCV718516

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.05%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -4.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	22.3	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 1.05% African / African-American · 787/75,012 alleles

Filtering AF 0.988% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.964%

Overall 0.0547% 883/1,613,788 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.05%	95
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0704%	1,420
Admixed American	0.0667%	1,499
South Asian	0.00329%	30,363
European (non-Finnish)	0.000339%	294,939

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.Asp696Asn
Coding: c.2086G>A
MANE Select: NM_000065
dbSNP: rs78888823
Type: single nucleotide variant
Location: chr5:41154987 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 696: the sushi 1 domain; the 'c5b-binding domain' region; the 'ccp 2' 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.Asp696Gly Benign/Likely benign ★★ same residue
C6 p.Asp696= Likely benign ★ same residue
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

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-asp696asn (accessed [today's date]).

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