Is C6 p.Ser545= (c.1635T>C) pathogenic?

C6 p.Ser545= (c.1635T>C) is classified Benign in C6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Low-frequency (popmax 3.89%, nfe).

How common is C6 p.Ser545= (c.1635T>C) in the general population?

C6 p.Ser545= (c.1635T>C) is low-frequency (popmax 3.89%, nfe) (gnomAD).

C6 p.Ser545=

c.1635T>C · rs62361567 · VCV1170885

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.89%, nfe)

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 -9.4	GERP -3.8
Overall
CADD	0.067	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.89% European (non-Finnish) · 45,904/1,179,696 alleles

Filtering AF 3.86% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.85%

Overall 3.22% 52,018/1,613,748 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.95%	25
European (non-Finnish)grpmax	3.89%	26
Remaining individualsnot grpmax-eligible	2.85%	35
Finnishnot grpmax-eligible	2.31%	43
Admixed American	1.95%	51
Middle Eastern	1.8%	56
Ashkenazi Jewishnot grpmax-eligible	0.939%	106
South Asian	0.904%	111
African / African-American	0.573%	174
East Asian	0.00891%	11,220

Amish 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: C6
Protein: p.Ser545=
Coding: c.1635T>C
MANE Select: NM_000065
dbSNP: rs62361567
Type: single nucleotide variant
Location: chr5:41160191 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 545: a disulfide bond; the egf-like domain

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C6 p.Ser545Asn Uncertain significance ★ ⚠ same residue
C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Arg606Ter Pathogenic ★★ same type
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Ala21Val Uncertain significance ★★ ⚠ same type
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same type
C6 p.Ala456Thr 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/c6-p-ser545 (accessed [today's date]).

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