Is C2 p.Val655= (c.1965C>T) pathogenic?

C2 p.Val655= (c.1965C>T) is classified Likely benign in C2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-23). Ultra-rare (popmax 0.0999%, afr).

How common is C2 p.Val655= (c.1965C>T) in the general population?

C2 p.Val655= (c.1965C>T) is ultra-rare (popmax 0.0999%, afr) (gnomAD).

C2 p.Val655=

c.1965C>T · rs141487807 · VCV1549553

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0999%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.043	moderately benign-leaning
Splicing
SpliceAI	Δ0.25	acceptor loss, 4 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.32	GERP -3.2
Overall
CADD	2.953	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0999% African / African-American · 75/75,058 alleles

Filtering AF 0.0817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.075%

Overall 0.00508% 82/1,613,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0999%	1,001
Admixed American	0.00833%	12,006
Remaining individualsnot grpmax-eligible	0.0032%	31,249

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.Val655=
Coding: c.1965C>T
MANE Select: NM_000063
dbSNP: rs141487807
Type: single nucleotide variant
Location: chr6:31944789 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 655: an α-helix; 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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C2 p.Ala363Thr Uncertain significance ★★ ⚠ same type
C2 p.Ala682Glu Uncertain significance ★★ ⚠ same type
C2 p.Arg124Gln Uncertain significance ★★ ⚠ same type
C2 p.Arg129His Uncertain significance ★★ ⚠ same type
C2 p.Arg174Cys Uncertain significance ★★ ⚠ same type
C2 p.Arg176Cys Uncertain significance ★★ ⚠ same type

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-val655 (accessed [today's date]).

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