Is SCRIB p.Ile918Val (c.2752A>G) pathogenic?

SCRIB p.Ile918Val (c.2752A>G) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-27). AlphaMissense: ambiguous (0.3688); Ultra-rare (popmax 0.017%, mid).

How common is SCRIB p.Ile918Val (c.2752A>G) in the general population?

SCRIB p.Ile918Val (c.2752A>G) is ultra-rare (popmax 0.017%, mid) (gnomAD).

What do computational predictors say about SCRIB p.Ile918Val (c.2752A>G)?

AlphaMissense predicts ambiguous (score 0.3688) — an in-silico prediction, not a clinical call.

SCRIB p.Ile918Val

c.2752A>G · rs372917457 · VCV2221256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3688	ambiguous
REVEL	0.158	moderately benign-leaning
SaProt	LLR -4.56	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.5, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	23.3	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 0.017% Middle Eastern · 1/5,898 alleles

Filtering AF 0.00537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00158% 25/1,579,304 alleles · ultra-rare exomes 16/1,430,916 · genomes 9/148,388 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,898
African / African-American	0.0109%	9,178
Admixed American	0.00536%	18,659
Remaining individualsnot grpmax-eligible	0.00488%	20,489
European (non-Finnish)	0.000855%	116,958

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.Ile918Val
Coding: c.2752A>G
MANE Select: NM_182706
dbSNP: rs372917457
Type: single nucleotide variant
Location: chr8:143804825 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 918: a β-strand; the pdz 2 domain; the 'interaction with arhgef7' region; the 'required for interaction with vim' 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-ile918val (accessed [today's date]).

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