Is SCRIB p.Arg1147Cys (c.3439C>T) pathogenic?

SCRIB p.Arg1147Cys (c.3439C>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: ambiguous (0.5079); Very rare (popmax 0.00777%, sas).

How common is SCRIB p.Arg1147Cys (c.3439C>T) in the general population?

SCRIB p.Arg1147Cys (c.3439C>T) is very rare (popmax 0.00777%, sas) (gnomAD).

What do computational predictors say about SCRIB p.Arg1147Cys (c.3439C>T)?

AlphaMissense predicts ambiguous (score 0.5079) — an in-silico prediction, not a clinical call.

SCRIB p.Arg1147Cys

c.3439C>T · VCV4160835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00777%, sas)

Computational evidence

Protein change
AlphaMissense	0.5079	ambiguous
REVEL	0.358	indeterminate
SaProt	LLR -13.94	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	23.9	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 0.00777% South Asian · 7/90,086 alleles

Filtering AF 0.00637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00653% 102/1,563,060 alleles · very rare exomes 92/1,416,130 · genomes 10/146,930 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00777%	12,869
European (non-Finnish)	0.00771%	12,971
African / African-American	0.0041%	24,377
Remaining individualsnot grpmax-eligible	0.00333%	30,032
Finnishnot grpmax-eligible	0.00195%	51,168

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.Arg1147Cys
Coding: c.3439C>T
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143803547 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1147: an α-helix; the pdz 4 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-arg1147cys (accessed [today's date]).

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