Is SERPING1 p.Pro489Ala (c.1465C>G) pathogenic?

SERPING1 p.Pro489Ala (c.1465C>G) is classified Uncertain significance in SERPING1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-06). AlphaMissense: ambiguous (0.3447); Very rare (popmax 0.00127%, nfe).

How common is SERPING1 p.Pro489Ala (c.1465C>G) in the general population?

SERPING1 p.Pro489Ala (c.1465C>G) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about SERPING1 p.Pro489Ala (c.1465C>G)?

AlphaMissense predicts ambiguous (score 0.3447) — an in-silico prediction, not a clinical call.

SERPING1 p.Pro489Ala

c.1465C>G · rs2495458621 · VCV2435815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3447 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3447	ambiguous
REVEL	0.605	indeterminate
SaProt	LLR -9.88	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 16 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 0.00127% European (non-Finnish) · 15/1,179,994 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,614,070 alleles · very rare exomes 15/1,461,762 · genomes 0/152,308 · joint denominator

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: SERPING1
Protein: p.Pro489Ala
Coding: c.1465C>G
MANE Select: NM_000062
dbSNP: rs2495458621
Type: single nucleotide variant
Location: chr11:57614543 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 5 PDB
Residue 489: a β-strand; 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.Pro489Arg Pathogenic ★ same residue
SERPING1 p.Pro489fs Likely 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
SERPING1 c.51+3A>G Pathogenic ★★ same type
SERPING1 c.52-1G>A Pathogenic ★★ same type
SERPING1 c.550+1G>A 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-pro489ala (accessed [today's date]).

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