Is C1S p.Ser654= (c.1962C>T) pathogenic?

C1S p.Ser654= (c.1962C>T) is classified Likely benign in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). Ultra-rare (popmax 0.0178%, eas).

How common is C1S p.Ser654= (c.1962C>T) in the general population?

C1S p.Ser654= (c.1962C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

C1S p.Ser654=

c.1962C>T · rs782191695 · VCV1938427

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -0.24, phastCons 0.97
Overall
CADD	9.002	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,886 alleles

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

Overall 0.000496% 8/1,613,830 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: C1S
Protein: p.Ser654=
Coding: c.1962C>T
MANE Select: NM_001734
dbSNP: rs782191695
Type: single nucleotide variant
Location: chr12:7070546 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 654: a β-strand; a disulfide bond; the peptidase s1 domain

Full C1S gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1S p.Arg523Ter Pathogenic ★★ same type
C1S c.1196-3C>T Uncertain significance ★★ same type
C1S c.717+5G>A Uncertain significance ★★ same type
C1S c.717+6T>A Uncertain significance ★★ same type
C1S p.Ala227Val Uncertain significance ★★ ⚠ same type
C1S p.Ala231Val Uncertain significance ★★ ⚠ same type
C1S p.Ala584Val Uncertain significance ★★ ⚠ same type
C1S p.Ala649Thr 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/c1s-p-ser654 (accessed [today's date]).

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