Is SCRIB p.Glu1392Ala (c.4175A>C) pathogenic?

SCRIB p.Glu1392Ala (c.4175A>C) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: ambiguous (0.4636); Very rare (popmax 0.00136%, nfe).

How common is SCRIB p.Glu1392Ala (c.4175A>C) in the general population?

SCRIB p.Glu1392Ala (c.4175A>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about SCRIB p.Glu1392Ala (c.4175A>C)?

AlphaMissense predicts ambiguous (score 0.4636) — an in-silico prediction, not a clinical call.

SCRIB p.Glu1392Ala

c.4175A>C · VCV4160858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4636	ambiguous
REVEL	0.295	indeterminate
SaProt	LLR -4.73	tolerated
Splicing
SpliceAI	Δ0.31	donor gain · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	28.3	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 0.00136% European (non-Finnish) · 16/1,172,454 alleles

Filtering AF 0.000808% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000654%

Overall 0.00101% 16/1,586,918 alleles · very rare exomes 16/1,434,850 · genomes 0/152,068 · joint denominator

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.Glu1392Ala
Coding: c.4175A>C
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143792710 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1392: 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-glu1392ala (accessed [today's date]).

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