Is SERPINE3 p.Phe259Leu (c.775T>C) pathogenic?

SERPINE3 p.Phe259Leu (c.775T>C) is classified Likely benign in SERPINE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). AlphaMissense: likely pathogenic (0.7207); Very rare (popmax 0.00447%, eas).

How common is SERPINE3 p.Phe259Leu (c.775T>C) in the general population?

SERPINE3 p.Phe259Leu (c.775T>C) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about SERPINE3 p.Phe259Leu (c.775T>C)?

AlphaMissense predicts likely pathogenic (score 0.7207) — an in-silico prediction, not a clinical call.

SERPINE3 p.Phe259Leu

c.775T>C · rs749085296 · VCV3160480

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7207	likely pathogenic · top 6% in SERPINE3
REVEL	0.224	benign-leaning
SaProt	LLR -11.01	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.6	GERP -3.2, phastCons 0.33
Regional constraint	o/e 0.89	unconstrained · MANE · 23 kb · p 0.02 · regional, not allelic
Overall
CADD	14.15	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 0.00447% East Asian · 2/44,782 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,611,692 alleles · very rare exomes 2/1,459,624 · genomes 1/152,068 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,391
European (non-Finnish)	8.48e-05%	1,179,094

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.Phe259Leu
Coding: c.775T>C
MANE Select: NM_001386375
dbSNP: rs749085296
Type: single nucleotide variant
Location: chr13:51348287 (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-phe259leu (accessed [today's date]).

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