Is C2 p.Ser498= (c.1494C>T) pathogenic?

C2 p.Ser498= (c.1494C>T) is classified Likely benign in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0111%, eas).

How common is C2 p.Ser498= (c.1494C>T) in the general population?

C2 p.Ser498= (c.1494C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

C2 p.Ser498=

c.1494C>T · rs774403540 · VCV1984231

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.049	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.1
Overall
CADD	0.518	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,896 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00384% 62/1,612,958 alleles · ultra-rare exomes 61/1,460,730 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,979
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.00381%	26,223

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.Ser498=
Coding: c.1494C>T
MANE Select: NM_000063
dbSNP: rs774403540
Type: single nucleotide variant
Location: chr6:31943454 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 498: a β-strand; the peptidase s1 domain

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

Similar variants

C2 p.Ser498Ala Uncertain significance ★ ⚠ same residue
C2 c.1902+5G>A Uncertain significance ★★ same type
C2 c.2029+5G>A Uncertain significance ★★ same type
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

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-ser498 (accessed [today's date]).

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