Is C1S p.Phe449Leu (c.1347C>A) pathogenic?

C1S p.Phe449Leu (c.1347C>A) is classified Uncertain significance in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-08). AlphaMissense: likely pathogenic (0.9498); Absent from gnomAD v4.1.

How common is C1S p.Phe449Leu (c.1347C>A) in the general population?

C1S p.Phe449Leu (c.1347C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C1S p.Phe449Leu (c.1347C>A)?

AlphaMissense predicts likely pathogenic (score 0.9498) — an in-silico prediction, not a clinical call.

C1S p.Phe449Leu

c.1347C>A · rs782547981 · VCV2826807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9498 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9498	likely pathogenic · top 6% in C1S
REVEL	0.57	indeterminate
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.59	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 3,608 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C1S
Protein: p.Phe449Leu
Coding: c.1347C>A
MANE Select: NM_001734
dbSNP: rs782547981
Type: single nucleotide variant
Location: chr12:7069931 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 449: 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-phe449leu (accessed [today's date]).

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