Is C2 p.Ala495fs (c.1483del) pathogenic?

C2 p.Ala495fs (c.1483del) is classified Likely pathogenic in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-19). Very rare (popmax 0.00267%, afr); Associated with C2-related disorder.

What condition is associated with C2 p.Ala495fs (c.1483del)?

C2 p.Ala495fs (c.1483del) is associated with C2-related disorder (ClinVar).

How common is C2 p.Ala495fs (c.1483del) in the general population?

C2 p.Ala495fs (c.1483del) is very rare (popmax 0.00267%, afr) (gnomAD).

C2 p.Ala495fs

c.1483del · VCV4974239

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

C2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	GERP -2.1, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,912 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000868% 14/1,612,888 alleles · very rare exomes 12/1,460,720 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-Americangrpmax	0.00267%	37,456
European (non-Finnish)	0.000847%	118,002

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala495fs
Coding: c.1483del
MANE Select: NM_000063
Type: Deletion
Location: chr6:31943438 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 495: a β-strand; the peptidase s1 domain

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

Disease context

C2-related disorder

Similar variants

C2 c.841_849+19del Pathogenic/Likely pathogenic ★★ same condition
C2 p.Pro207fs Likely pathogenic ★ same condition
C2 p.Ser80fs Pathogenic ★ same condition
C2 p.Ala495Pro Uncertain significance ★ ⚠ same residue
C2 p.Ala495Val Uncertain significance ★ ⚠ same residue
C2 p.Ser186Cys Uncertain significance ★ ⚠ same condition
ZBTB12 p.Ile80= Benign ★ same condition
C2 c.1455+17del Benign/Likely benign ★★ 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-ala495fs (accessed [today's date]).

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