Is C1S p.Glu412Asp (c.1236G>C) pathogenic?

C1S p.Glu412Asp (c.1236G>C) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.0763); Rare (popmax 0.107%, amr); Associated with Inborn genetic diseases.

What condition is associated with C1S p.Glu412Asp (c.1236G>C)?

C1S p.Glu412Asp (c.1236G>C) is associated with Inborn genetic diseases (ClinVar).

How common is C1S p.Glu412Asp (c.1236G>C) in the general population?

C1S p.Glu412Asp (c.1236G>C) is rare (popmax 0.107%, amr) (gnomAD).

What do computational predictors say about C1S p.Glu412Asp (c.1236G>C)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

C1S p.Glu412Asp

c.1236G>C · rs199547819 · VCV1373697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.53	GERP -3.7
Regional constraint	o/e 0.79	unconstrained · MANE · 3,608 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	2.58	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.107% Admixed American · 64/60,024 alleles

Filtering AF 0.0856% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.078%

Overall 0.00434% 70/1,613,986 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.107%	938
Remaining individualsnot grpmax-eligible	0.0048%	20,836
African / African-American	0.004%	25,003

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.Glu412Asp
Coding: c.1236G>C
MANE Select: NM_001734
dbSNP: rs199547819
Type: single nucleotide variant
Location: chr12:7068496 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 412: a turn; a disulfide bond; the sushi 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C1S p.Glu412= Likely benign ★ same residue
C1S p.Ala227Val Uncertain significance ★★ ⚠ same condition
C1S p.Ala231Val Uncertain significance ★★ ⚠ same condition
C1S p.Ala649Thr Uncertain significance ★★ ⚠ same condition
C1S p.Arg207Gln Uncertain significance ★★ ⚠ same condition
C1S p.Arg286Cys Uncertain significance ★★ ⚠ same condition
C1S p.Arg481Gly Uncertain significance ★★ ⚠ same condition
C1S p.Arg496Gln Uncertain significance ★★ ⚠ same condition

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-glu412asp (accessed [today's date]).

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