Is SERPINE1 p.His25Pro (c.74A>C) pathogenic?

SERPINE1 p.His25Pro (c.74A>C) is classified Likely benign in SERPINE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-12). AlphaMissense: likely benign (0.0609); Rare (popmax 0.107%, afr).

How common is SERPINE1 p.His25Pro (c.74A>C) in the general population?

SERPINE1 p.His25Pro (c.74A>C) is rare (popmax 0.107%, afr) (gnomAD).

What do computational predictors say about SERPINE1 p.His25Pro (c.74A>C)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

SERPINE1 p.His25Pro

c.74A>C · rs2227647 · VCV1123294

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -4.99	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 -0.28	GERP -2.4
Regional constraint	o/e 0.86	unconstrained · MANE · 9,045 bp · p 0.0014 · regional, not allelic
Overall
CADD	1.13	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 0.107% African / African-American · 80/75,020 alleles

Filtering AF 0.0877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0808%

Overall 0.00545% 88/1,614,120 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.107%	938
Admixed American	0.00666%	15,004
Remaining individualsnot grpmax-eligible	0.0064%	15,627

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: SERPINE1
Protein: p.His25Pro
Coding: c.74A>C
MANE Select: NM_000602
dbSNP: rs2227647
Type: single nucleotide variant
Location: chr7:101128467 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.03 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.68 · 29 PDB
Residue 25: a UniProt-annotated variant site (in)

Full SERPINE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SERPINE1 c.*617T>A Uncertain significance ★★ same type
SERPINE1 p.Asp240Gly Uncertain significance ★★ ⚠ same type
SERPINE1 p.Gly196Ser Uncertain significance ★★ ⚠ same type
SERPINE1 p.Leu175Pro Uncertain significance ★★ ⚠ same type
SERPINE1 p.Phe157Leu Uncertain significance ★★ ⚠ same type
SERPINE1 p.Pro372Ala Uncertain significance ★★ ⚠ same type
SERPINE1 c.1088-106A>G Benign ★★ same type
SERPINE1 c.1088-9C>T Benign/Likely benign ★★ 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/serpine1-p-his25pro (accessed [today's date]).

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