Is SCRIB p.Pro1592Leu (c.4775C>T) pathogenic?

SCRIB p.Pro1592Leu (c.4775C>T) is classified Likely benign in SCRIB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-30). AlphaMissense: likely benign (0.1475); Rare (popmax 0.248%, afr).

How common is SCRIB p.Pro1592Leu (c.4775C>T) in the general population?

SCRIB p.Pro1592Leu (c.4775C>T) is rare (popmax 0.248%, afr) (gnomAD).

What do computational predictors say about SCRIB p.Pro1592Leu (c.4775C>T)?

AlphaMissense predicts likely benign (score 0.1475) — an in-silico prediction, not a clinical call.

SCRIB p.Pro1592Leu

c.4775C>T · rs149841848 · VCV732325

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1475 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.248%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1475	likely benign
REVEL	0.201	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.4	GERP 1.5, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1567L vs ClinVar P1592L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.248% African / African-American · 186/74,982 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.208%

Overall 0.0175% 282/1,610,684 alleles · rare exomes 164/1,458,354 · genomes 118/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.248%	403
South Asian	0.054%	1,851
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.0256%	3,899
Admixed American	0.0151%	6,644
East Asian	0.00447%	22,353
European (non-Finnish)	0.00153%	65,505

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.Pro1592Leu
Coding: c.4775C>T
MANE Select: NM_182706
dbSNP: rs149841848
Type: single nucleotide variant
Location: chr8:143791436 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB

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-pro1592leu (accessed [today's date]).

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