Is SCRIB p.Pro539Leu (c.1616C>T) pathogenic?

SCRIB p.Pro539Leu (c.1616C>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely benign (0.0638); Ultra-rare (popmax 0.0165%, mid).

How common is SCRIB p.Pro539Leu (c.1616C>T) in the general population?

SCRIB p.Pro539Leu (c.1616C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SCRIB p.Pro539Leu (c.1616C>T)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

SCRIB p.Pro539Leu

c.1616C>T · rs760633347 · VCV2487580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.16	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 -1.3	GERP -3
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	1.975	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 0.0165% Middle Eastern · 1/6,048 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00168% 27/1,610,874 alleles · ultra-rare exomes 25/1,458,684 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,048
South Asian	0.00439%	22,772
East Asian	0.00223%	44,886
Finnishnot grpmax-eligible	0.00164%	61,066
European (non-Finnish)	0.00161%	62,102
Remaining individualsnot grpmax-eligible	0.0016%	62,450

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.Pro539Leu
Coding: c.1616C>T
MANE Select: NM_182706
dbSNP: rs760633347
Type: single nucleotide variant
Location: chr8:143809633 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 539: the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' region; 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-pro539leu (accessed [today's date]).

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