Is SCRIB p.Pro1332Leu (c.3995C>T) pathogenic?

SCRIB p.Pro1332Leu (c.3995C>T) is classified Benign in SCRIB (ClinVar, Single submitter, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0617); Rare (popmax 0.839%, nfe).

How common is SCRIB p.Pro1332Leu (c.3995C>T) in the general population?

SCRIB p.Pro1332Leu (c.3995C>T) is rare (popmax 0.839%, nfe) (gnomAD).

What do computational predictors say about SCRIB p.Pro1332Leu (c.3995C>T)?

AlphaMissense predicts likely benign (score 0.0617) — an in-silico prediction, not a clinical call.

SCRIB p.Pro1332Leu

c.3995C>T · rs202137464 · VCV2658911

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0617 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.839%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0617	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP 0.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	17.58	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 0.839% European (non-Finnish) · 9,470/1,129,380 alleles

Filtering AF 0.824% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.819%

Overall 0.712% 10,773/1,514,076 alleles · rare exomes 9,942/1,361,724 · genomes 831/152,352 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.23%	81
European (non-Finnish)grpmax	0.839%	119
Amishnot grpmax-eligible	0.439%	228
Remaining individualsnot grpmax-eligible	0.412%	243
South Asian	0.207%	484
Middle Eastern	0.19%	527
Admixed American	0.172%	581
African / African-American	0.106%	946
Ashkenazi Jewishnot grpmax-eligible	0.0986%	1,014
East Asian	0.00732%	13,667

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SCRIB
Protein: p.Pro1332Leu
Coding: c.3995C>T
MANE Select: NM_182706
dbSNP: rs202137464
Type: single nucleotide variant
Location: chr8:143792998 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1332: the 'disordered' region

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

Similar variants

SCRIB c.3120+10C>G Benign/Likely benign ★★ same type
SCRIB c.504-9C>T Benign ★★ same type
SCRIB p.Ala1488= Likely benign ★★ same type
SCRIB p.Arg492= Benign ★★ same type
SCRIB p.Asn647= Benign/Likely benign ★★ same type
SCRIB p.Leu254= Benign ★★ same type
SCRIB p.Phe571= Benign ★★ same type
SCRIB p.Pro1343= 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/scrib-p-pro1332leu (accessed [today's date]).

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