Is SCRIB p.Val1380Leu (c.4138G>T) pathogenic?

SCRIB p.Val1380Leu (c.4138G>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely pathogenic (0.8436); Ultra-rare (popmax 0.031%, amr).

How common is SCRIB p.Val1380Leu (c.4138G>T) in the general population?

SCRIB p.Val1380Leu (c.4138G>T) is ultra-rare (popmax 0.031%, amr) (gnomAD).

What do computational predictors say about SCRIB p.Val1380Leu (c.4138G>T)?

AlphaMissense predicts likely pathogenic (score 0.8436) — an in-silico prediction, not a clinical call.

SCRIB p.Val1380Leu

c.4138G>T · rs151186632 · VCV2507806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8436 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.031%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8436	likely pathogenic
REVEL	0.093	moderately benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.20	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	23.2	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 0.031% Admixed American · 18/58,154 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.019% 303/1,592,236 alleles · ultra-rare exomes 288/1,440,020 · genomes 15/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.031%	3,231
European (non-Finnish)	0.0229%	4,362
Remaining individualsnot grpmax-eligible	0.0178%	5,614
East Asian	0.00451%	22,189
African / African-American	0.00402%	24,901

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.Val1380Leu
Coding: c.4138G>T
MANE Select: NM_182706
dbSNP: rs151186632
Type: single nucleotide variant
Location: chr8:143792747 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1380: 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-val1380leu (accessed [today's date]).

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