Is SERPINE3 p.Arg23Cys (c.67C>T) pathogenic?

SERPINE3 p.Arg23Cys (c.67C>T) is classified Uncertain significance in SERPINE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely benign (0.1441); Very rare (popmax 0.00678%, nfe).

How common is SERPINE3 p.Arg23Cys (c.67C>T) in the general population?

SERPINE3 p.Arg23Cys (c.67C>T) is very rare (popmax 0.00678%, nfe) (gnomAD).

What do computational predictors say about SERPINE3 p.Arg23Cys (c.67C>T)?

AlphaMissense predicts likely benign (score 0.1441) — an in-silico prediction, not a clinical call.

SERPINE3 p.Arg23Cys

c.67C>T · rs376407383 · VCV3160479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00678%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1441	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.58	GERP 0.4
Regional constraint	o/e 0.89	unconstrained · MANE · 23 kb · p 0.02 · regional, not allelic
Overall
CADD	19.69	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 0.00678% European (non-Finnish) · 80/1,179,880 alleles

Filtering AF 0.00555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.0052% 84/1,613,908 alleles · very rare exomes 76/1,461,684 · genomes 8/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00678%	14,749
Remaining individualsnot grpmax-eligible	0.0032%	31,233
African / African-American	0.00133%	74,934
South Asian	0.0011%	91,090

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.Arg23Cys
Coding: c.67C>T
MANE Select: NM_001386375
dbSNP: rs376407383
Type: single nucleotide variant
Location: chr13:51341158 (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.Arg369Thr Uncertain significance ★ same type
SERPINE3 p.Arg371Gln Uncertain significance ★ ⚠ same type
SERPINE3 p.Arg379Gln 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-arg23cys (accessed [today's date]).

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