Is SERPINE3 p.Pro324Leu (c.971C>T) pathogenic?

SERPINE3 p.Pro324Leu (c.971C>T) is classified Uncertain significance in SERPINE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.2506); Very rare (popmax 0.0022%, nfe).

How common is SERPINE3 p.Pro324Leu (c.971C>T) in the general population?

SERPINE3 p.Pro324Leu (c.971C>T) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about SERPINE3 p.Pro324Leu (c.971C>T)?

AlphaMissense predicts likely benign (score 0.2506) — an in-silico prediction, not a clinical call.

SERPINE3 p.Pro324Leu

c.971C>T · VCV4162964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2506 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2506	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -10.34	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 23 kb · p 0.02 · regional, not allelic
Overall
CADD	25.2	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 0.0022% European (non-Finnish) · 25/1,138,318 alleles

Filtering AF 0.00151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00127%

Overall 0.00168% 26/1,543,802 alleles · very rare exomes 24/1,391,654 · genomes 2/152,148 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,533
Remaining individualsnot grpmax-eligible	0.00167%	59,890

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: SERPINE3
Protein: p.Pro324Leu
Coding: c.971C>T
MANE Select: NM_001386375
Type: single nucleotide variant
Location: chr13:51355114 (GRCh38)
Gene constraint: LOEUF 1.45 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.41

Full SERPINE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SERPINE3 p.Ala255Ser Uncertain significance ★ ⚠ same type
SERPINE3 p.Ala34Ser Uncertain significance ★ ⚠ same type
SERPINE3 p.Ala377Val Uncertain significance ★ ⚠ same type
SERPINE3 p.Ala43Thr Uncertain significance ★ ⚠ same type
SERPINE3 p.Ala68Thr Uncertain significance ★ ⚠ same type
SERPINE3 p.Arg23Cys Uncertain significance ★ ⚠ same type
SERPINE3 p.Arg369Thr Uncertain significance ★ same type
SERPINE3 p.Arg371Gln 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/serpine3-p-pro324leu (accessed [today's date]).

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