Is SERPING1 p.Pro34Thr (c.100C>A) pathogenic?

SERPING1 p.Pro34Thr (c.100C>A) is classified Uncertain significance in SERPING1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-09-25). AlphaMissense: likely benign (0.0614); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary angioedema with C1Inh deficiency.

What condition is associated with SERPING1 p.Pro34Thr (c.100C>A)?

SERPING1 p.Pro34Thr (c.100C>A) is associated with hereditary angioedema with C1Inh deficiency (ClinVar).

How common is SERPING1 p.Pro34Thr (c.100C>A) in the general population?

SERPING1 p.Pro34Thr (c.100C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hereditary angioedema with C1Inh deficiency inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SERPING1 p.Pro34Thr (c.100C>A)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

SERPING1 p.Pro34Thr

c.100C>A · rs781444611 · VCV1299728

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary angioedema with C1Inh deficiency

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -6.20	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 -0.5	GERP -1.4
Regional constraint	o/e 0.83	unconstrained · MANE · 16 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	16.09	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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,052 alleles · very rare exomes 0/1,461,886 · genomes 1/152,166 · 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.Pro34Thr
Coding: c.100C>A
MANE Select: NM_000062
dbSNP: rs781444611
Type: single nucleotide variant
Location: chr11:57599927 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 5 PDB
Residue 34: the 'disordered' region

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

Disease context

hereditary angioedema with C1Inh deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary angioedema with C1Inh deficiency (Orphanet):

Inheritance: Not applicable
Onset: Adult, Elderly

Similar variants

SERPING1 p.Pro34Ala Uncertain significance ★ ⚠ same residue
SERPING1 p.Gln180Ter Pathogenic ★ same condition
SERPING1 p.Leu398Arg Pathogenic ★ same condition
SERPING1 p.Leu430Arg Pathogenic ★ same condition
SERPING1 p.Pro34fs Pathogenic ★ same residue
SERPING1 c.1249+2T>C Pathogenic same condition
SERPING1 c.550+1G>T Pathogenic same condition
SERPING1 p.Gln474His Likely pathogenic ⚠ 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/serping1-p-pro34thr (accessed [today's date]).

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