Is C2 p.Trp699Cys (c.2097G>C) pathogenic?

C2 p.Trp699Cys (c.2097G>C) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-25). AlphaMissense: likely pathogenic (0.994); Ultra-rare (popmax 0.0178%, eas).

How common is C2 p.Trp699Cys (c.2097G>C) in the general population?

C2 p.Trp699Cys (c.2097G>C) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about C2 p.Trp699Cys (c.2097G>C)?

AlphaMissense predicts likely pathogenic (score 0.994) — an in-silico prediction, not a clinical call.

C2 p.Trp699Cys

c.2097G>C · rs754270238 · VCV1510880

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.994	likely pathogenic · top 1% in C2
REVEL	0.495	indeterminate
SaProt	LLR -15.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.26	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	33.0	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 0.0178% East Asian · 8/44,896 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,612,734 alleles · ultra-rare

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: C2
Protein: p.Trp699Cys
Coding: c.2097G>C
MANE Select: NM_000063
dbSNP: rs754270238
Type: single nucleotide variant
Location: chr6:31945195 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 699: a β-strand; a disulfide bond; the peptidase s1 domain

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/c2-p-trp699cys (accessed [today's date]).

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