Is SERPING1 p.Arg466Pro (c.1397G>C) pathogenic?

SERPING1 p.Arg466Pro (c.1397G>C) is classified Pathogenic in SERPING1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-28). AlphaMissense: likely pathogenic (0.9672); Absent from gnomAD v4.1.

How common is SERPING1 p.Arg466Pro (c.1397G>C) in the general population?

SERPING1 p.Arg466Pro (c.1397G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SERPING1 p.Arg466Pro (c.1397G>C)?

AlphaMissense predicts likely pathogenic (score 0.9672) — an in-silico prediction, not a clinical call.

SERPING1 p.Arg466Pro

c.1397G>C · rs121907948 · VCV426171

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9672 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9672	likely pathogenic ✓ concordant with ClinVar · top 1% in SERPING1
REVEL	0.644	pathogenic-leaning
SaProt	LLR -12.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 16 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	27.3	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: SERPING1
Protein: p.Arg466Pro
Coding: c.1397G>C
MANE Select: NM_000062
dbSNP: rs121907948
Type: single nucleotide variant
Location: chr11:57614475 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 5 PDB
Residue 466: a functional site (reactive bond for chymotrypsin); a functional site (cleavage; by c1s); a functional site (reactive bond); a UniProt-annotated variant site (in hae1; phenotype consistent with hereditary angioedema type 2)

Full SERPING1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SERPING1 p.Arg466Cys Pathogenic ★★ same residue
SERPING1 p.Arg466Gly Pathogenic ★★ same residue
SERPING1 p.Arg466Leu Likely pathogenic ★ same residue
SERPING1 p.Arg466His Conflicting classifications of pathogenicity ★ ⚠ same residue
SERPING1 p.Arg466Ser Pathogenic same residue
SERPING1 c.1030-1G>T Pathogenic ★★ same type
SERPING1 c.51+1G>T Pathogenic ★★ same type
SERPING1 c.51+3A>C Pathogenic/Likely pathogenic ★★ 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/serping1-p-arg466pro (accessed [today's date]).

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